Phenoxymethyl heterocyclic compounds

ABSTRACT

Phenoxymethyl compounds that inhibit at least one phosphodiesterase 10 are described as are pharmaceutical compositions containing such compounds an methods for treating various CNS disorders by administering such compounds to a patient in need thereof.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of U.S. patent applicationSer. No. 12/642,026, filed Dec. 18, 2009, now U.S. Pat. No. 8,343,973,entitled “Phenoxymethyl Heterocyclic Compounds,” which claims thebenefit of priority under 35 U.S.C. §119(e) to U.S. Provisional PatentApplication No. 61/176,413, filed May 7, 2009, entitled “VicinalSubstituted Heterocyclic Compounds.” The entire contents of thesepriority applications are incorporated herein by reference.

BACKGROUND

Cyclic phosphodiesterases are intracellular enzymes which, through thehydrolysis of cyclic nucleotides cAMP and cGMP, regulate the levels ofthese mono phosphate nucleotides which serve as second messengers in thesignaling cascade of G-protein coupled receptors. In neurons, PDEs alsoplay a role in the regulation of downstream cGMP and cAMP dependentkinases which phosphorylate proteins involved in the regulation ofsynaptic transmission and homeostasis. To date, eleven different PDEfamilies have been identified which are encoded by 21 genes. The PDEscontain a variable N-terminal regulatory domain and a highly conservedC-terminal catalytic domain and differ in their substrate specificity,expression and localization in cellular and tissue compartments,including the CNS.

The discovery of a new PDE family, PDE10, was reported simultaneously bythree groups in 1999 (Soderling et al. “Isolation and characterizationof a dual-substrate phosphodiesterase gene family: PDE10A” Proc. Natl.Sci. 1999, 96, 7071-7076; Loughney et al. “Isolation andcharacterization of PDE10A, a novel human 3′,5′-cyclic nucleotidephosphodiesterase” Gene 1999, 234, 109-117; Fujishige et al. “Cloningand characterization of a novel human phosphodiesterase that hydrolyzesboth cAMP and cGMP (PDE10A)” J. Biol. Chem. 1999, 274, 18438-18445). Thehuman PDE10 sequence is highly homologous to both the rat and mousevariants with 95% amino acid identity overall, and 98% identityconserved in the catalytic region.

PDE10 is primarily expressed in the brain (caudate nucleus and putamen)and is highly localized in the medium spiny neurons of the striatum,which is one of the principal inputs to the basal ganglia. Thislocalization of PDE10 has led to speculation that it may influence thedopaminergic and glutamatergic pathways both which play roles in thepathology of various psychotic and neurodegenerative disorders.

PDE10 hydrolyzes both cAMP (K_(m)=0.05 uM) and cGMP (K_(m)=3 uM)(Soderling et al. “Isolation and Characterization of a dual-substratephosphodiesterase gene family: PDE10.” Proc. Natl. Sci. USA 1999,96(12), 7071-7076). In addition, PDE10 has a five-fold greater V_(max)for cGMP than for cAMP and these in vitro kinetic data have lead to thespeculation that PDE10 may act as a cAMP-inhibited cGMPphosphodiesterase in vivo (Soderling and Beavo “Regulation of cAMP andcGMP signaling: New phosphodiesterases and new functions,” Curr. Opin.Cell Biol., 2000, 12, 174-179).

PDE10 is also one of five phosphodiesterase members to contain a tandemGAF domain at their N-terminus. It is differentiated by the fact thatthe other GAF containing PDEs (PDE2, 5, 6, and 11) bind cGMP whilerecent data points to the tight binding of cAMP to the GAF domain ofPDE10 (Handa et al. “Crystal structure of the GAF-B domain from humanphosphodiesterase 10A complexed with its ligand, cAMP” J. Biol. Chem.2008, May 13^(th), ePub).

PDE10 inhibitors have been disclosed for the treatment of a variety ofneurological and psychiatric disorders including Parkinson's disease,schizophrenia, Huntington's disease, delusional disorders, drug-inducedpsychoses, obsessive compulsive and panic disorders (US PatentApplication 2003/0032579). Studies in rats (Kostowski et. al “Papaverinedrug induced stereotypy and catalepsy and biogenic amines in the brainof the rat” Pharmacol. Biochem. Behav. 1976, 5, 15-17) have showed thatpapaverine, a selective PDE10 inhibitor, reduces apomorphine inducedstereotypies and rat brain dopamine levels and increases haloperidolinduced catalepsy. This experiment lends support to the use of a PDE10inhibitor as an antipsychotic since similar trends are seen with known,marketed antipsychotics.

Antipsychotic medications are the mainstay of current treatment forschizophrenia. Conventional or classic antipsychotics, typified byhaloperidol, were introduced in the mid-1950s and have a proven trackrecord over the last half century in the treatment of schizophrenia.While these drugs are effective against the positive, psychotic symptomsof schizophrenia, they show little benefit in alleviating negativesymptoms or the cognitive impairment associated with the disease. Inaddition, drugs such as haloperidol have extreme side effects such asextrapyramidal symptoms (EPS) due to their specific dopamine D2 receptorinteraction. An even more severe condition characterized by significant,prolonged, abnormal motor movements known as tardive dyskinesia also mayemerge with prolonged classic antipsychotic treatment.

The 1990s saw the development of several new drugs for schizophrenia,referred to as atypical antipsychotics, typified by risperidone andolanzapine and most effectively, clozapine. These atypicalantipsychotics are generally characterized by effectiveness against boththe positive and negative symptoms associated with schizophrenia, buthave little effectiveness against cognitive deficiencies and persistingcognitive impairment remain a serious public health concern (Davis, J. Met al. “Dose response and dose equivalence of antipsychotics.” Journalof Clinical Psychopharmacology, 2004, 24 (2), 192-208; Friedman, J. H.et al “Treatment of psychosis in Parkinson's disease: Safetyconsiderations.” Drug Safety, 2003, 26 (9), 643-659). In addition, theatypical antipsychotic agents, while effective in treating the positiveand, to some degree, negative symptoms of schizophrenia, havesignificant side effects. For example, clozapine which is one of themost clinically effective antipsychotic drugs shows agranulocytosis inapproximately 1.5% of patients with fatalities due to this side effectbeing observed. Other atypical antipsychotic drugs have significant sideeffects including metabolic side effects (type 2 diabetes, significantweight gain, and dyslipidemia), sexual dysfunction, sedation, andpotential cardiovascular side effects that compromise their clinicallyeffectiveness. In the large, recently published NIH sponsored CATIEstudy, (Lieberman et al “The Clinical Antipsychotic Trials OfIntervention Effectiveness (CATIE) Schizophrenia Trial: clinicalcomparison of subgroups with and without the metabolic syndrome.”Schizophrenia Research, 2005, 80 (1), 9-43) 74% of patients discontinueduse of their antipsychotic medication within 18 months due to a numberof factors including poor tolerability or incomplete efficacy.Therefore, a substantial clinical need still exists for more effectiveand better tolerated antipsychotic mediations possibly through the useof PDE10 inhibitors.

BRIEF SUMMARY

The disclosure relates compounds which are inhibitors ofphosphodiesterase 10. The disclosure further relates to processes,pharmaceutical compositions, pharmaceutical preparations andpharmaceutical use of the compounds in the treatment of mammals,including human(s) for central nervous system (CNS) disorders and otherdisorders which may affect CNS function. The disclosure also relates tomethods for treating neurological, neurodegenerative and psychiatricdisorders including but not limited to those comprising cognitivedeficits or schizophrenic symptoms.

Described herein are compounds of Formula (I) that are inhibitors of atleast one phosphodiesterase 10:

wherein:HET is a heterocyclic ring selected from Formulas A29, A31 and A39 below

and the left most radical is connected to the X group;X is selected from optionally substituted aryl and optionallysubstituted heteroaryl;Z is optionally substituted heteroaryl;each R₂ is independently selected from C₁-C₄ alkyl, or two R₂ groupstaken together with the carbon to which they are attached form a 3membered cycloalkyl ring.

In one embodiment, alkyl groups are fully saturated whether present ontheir own or as part of another group (e.g. alkylamino or alkoxy).

In certain embodiments, substituent groups are not further substituted.

In various embodiments, any group that is defined as being optionallysubstituted can be singly or independently multiply optionallysubstituted.

In one embodiment, HET is selected from Formulas A29 and A31.

In another embodiment, HET is Formula A29.

In another embodiment, HET is Formula A31.

In one embodiment, X is selected from a monocyclic heteroaryl having 5ring atoms selected from C, O, S and N provided the total number of ringheteroatoms is less than or equal to four and where no more than one ofthe total number of heteroatoms is oxygen or sulfur, and a monocyclicaromatic ring having 6 atoms selected from C and N provided that notmore than 3 ring atoms are N, and where said ring may be optionally andindependently substituted with up to two groups selected from C₁-C₄alkyl, cycloalkyl, cycloalkyloxy, C₁-C₄ alkoxy, CF₃, carboxy,alkoxyalkyl, C₁-C₄ cycloalkylalkoxy, amino, alkylamino, dialkylamino,amido, alkylamido, dialkylamido, thioalkyl, halogen, cyano,alkylsulfonyl and nitro. Examples include but are not limited to1H-pyrrolyl, furanyl, thiophenyl, imidazolyl, pyrazolyl, isothiazolyl,isoxazolyl, oxazolyl, thiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl,1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, tetrazolyl,1,2,3,4-oxatriazolyl, 1,2,3,5-oxatriazolyl, 1,2,3,4-thiatriazolyl,1,2,3,5-thiatriazolyl, 1,2,3-triazinyl, 1,2,4-triazinyl,1,3,5-triazinyl, pyridinyl, pyrazinyl, pyridazinyl and pyrimidinyl.

In a further embodiment, X is a monocyclic heteroaryl having 6 ringatoms selected from C and N provided that not more than 3 ring atoms areN, and where said ring may be optionally and independently substitutedwith up to two groups selected from C₁-C₄ alkyl, cycloalkyl,cycloalkyloxy, C₁-C₄ alkoxy, CF₃, carboxy, alkoxyalkyl, C₁-C₄cycloalkylalkoxy, amino, alkylamino, dialkylamino, amido, alkylamido,dialkylamido, thioalkyl, halogen, cyano, alkylsulfonyl and nitro.Examples include but are not limited to 1,2,3-triazinyl,1,2,4-triazinyl, 1,3,5-triazinyl, pyridinyl, pyrazinyl, pyridazinyl andpyrimidinyl.

In a further embodiment, X is a monocyclic heteroaryl having 5 ringatoms selected from C, O, S, and N, provided the total number of ringheteroatoms is less than or equal to four and where no more than one ofthe total number of heteroatoms is oxygen or sulfur and where said ringmay be optionally and independently substituted with up to two groupsselected from C₁-C₄ alkyl, cycloalkyl, cycloalkyloxy, C₁-C₄ alkoxy, CF₃,carboxy, alkoxyalkyl, C₁-C₄ cycloalkylalkoxy, amino, alkylamino,dialkylamino, amido, alkylamido, dialkylamido, thioalkyl, halogen,cyano, alkylsulfonyl and nitro. Examples include but are not limited to1H-pyrrolyl, furanyl, thiophenyl, imidazolyl, pyrazolyl, isothiazolyl,isoxazolyl, oxazolyl, thiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl,1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, tetrazolyl,1,2,3,4-oxatriazolyl, 1,2,3,5-oxatriazolyl, 1,2,3,4-thiatriazolyl,1,2,3,5-thiatriazolyl.

In a further embodiment, X is 4-pyridinyl optionally substituted withone group selected from C₁-C₄ alkyl, cyclopropyl, cyclopropyloxy,cyclopropylmethyl, C₁-C₄ alkoxy, CF₃, amino, alkylamino, dialkylamino,thioalkyl, halogen, alkylsulfonyl and cyano.

In a further embodiment, X is 4-pyridinyl.

In another embodiment X is selected from restricted phenyl.

In a further embodiment, X is selected from a 3,4-disubstituted phenyl,4-substituted phenyl. and 4-pyridinyl.

In a further embodiment, X is selected from a 3,4-disubstituted phenyland 4-substituted phenyl.

In another embodiment, X is selected from 4-pyridinyl and 4-substitutedphenyl.

In an additional embodiment, X is 4-substituted phenyl.

In a further embodiment, X is 4-methoxyphenyl.

In another embodiment, X is 4-chlorophenyl.

In another embodiment, X is 4-cyanophenyl.

In one embodiment, Z is heteroaryl but is not quinolinyl or pyridyl.

In one embodiment, Z is heteroaryl but is not quinolinyl.

In one embodiment, Z is heteroaryl but is not pyridyl.

In one embodiment, Z is not pyridin-2-yl.

In one embodiment, Z is not pyridinyl.

In another embodiment, Z is selected from pyridin-2-yl,imidazo[1,2-a]pyridin-2-yl, imidazo[1,2-b]pyridazin-2-yl, andimidazo[1,2-b]pyridazin-6-yl all of which may be optionally substitutedwith up to 2 substituents independently selected from C₁-C₄ alkyl,cycloalkyl, cycloalkyloxy, C₁-C₄ alkoxy, CF₃, carboxy, alkoxyalkyl,C₁-C₄ cycloalkylalkoxy, amino, alkylamino, dialkylamino, amido,alkylamido, dialkylamido, thioalkyl, halogen, cyano, alkylsulfonyl andnitro.

In a further embodiment, Z is selected from imidazo[1,2-a]pyridin-2-yl,imidazo[1,2-b]pyridazin-2-yl, and imidazo[1,2-b]pyridazin-6-yl all ofwhich may be optionally substituted with up to 2 substituentsindependently selected from C₁-C₄ alkyl, C₁-C₄ alkoxy, C₃-C₆ cycloalkyl,C₃-C₆ cycloalkyloxy, cycloalkylalkyl, cycloalkylalkoxy, halogen,alkylsulfonyl and cyano.

In a further embodiment, Z is a 3,5-disubstituted-pyridin-2-yl with eachsubstituent being independently selected from C₁-C₄ alkyl, C₁-C₄ alkoxy,C₃-C₆ cycloalkyl, C₃-C₆ cycloalkyloxy, cycloalkylalkyl,cycloalkylalkoxy, halogen, alkylsulfonyl and cyano.

In a further embodiment, Z is 5-substituted-pyridin-2-yl with thesubstituent being independently selected from C₁-C₄ alkyl, C₁-C₄ alkoxy,C₃-C₆ cycloalkyl, C₃-C₆ cycloalkyloxy, cycloalkylalkyl,cycloalkylalkoxy, halogen, alkylsulfonyl and cyano.

In an additional embodiment, Z is imidazo[1,2-a]pyridin-2-yl substitutedwith up to 2 substituents independently selected from C₁-C₄ alkyl, C₁-C₄alkoxy, C₃-C₆ cycloalkyl, C₃-C₆ cycloalkyloxy, cycloalkylalkyl,cycloalkylalkoxy, halogen, alkylsulfonyl and cyano.

In an additional embodiment, Z is imidazo[1,2-b]pyridazin-2-ylsubstituted with up to 2 substituents independently selected from C₁-C₄alkyl, C₁-C₄ alkoxy, C₃-C₆ cycloalkyl, C₃-C₆ cycloalkyloxy,cycloalkylalkyl, cycloalkylalkoxy, halogen, alkylsulfonyl and cyano.

In an additional embodiment, Z is imidazo[1,2-b]pyridazin-6-ylsubstituted with up to 2 substituents independently selected from C₁-C₄alkyl, C₁-C₄ alkoxy, C₃-C₆ cycloalkyl, C₃-C₆ cycloalkyloxy,cycloalkylalkyl, cycloalkylalkoxy, halogen, alkylsulfonyl and cyano.

In a further embodiment, any Z substituent may be unsubstituted.

In one embodiment, R₂ is C₁-C₄ alkyl.

In another embodiment, R₂ is methyl.

In another embodiment, two R₂ groups taken together form a 3 memberedcycloalkyl ring.

Compounds of the disclosure may contain asymmetric centers and exist asdifferent enantiomers or diastereomers or a combination of thesetherein. All enantiomeric, diastereomeric forms of Formula (I) areembodied herein.

Compounds in the disclosure may be in the form of pharmaceuticallyacceptable salts. The phrase “pharmaceutically acceptable” refers tosalts prepared from pharmaceutically acceptable non-toxic bases andacids, including inorganic and organic bases and inorganic and organicacids. Salts derived from inorganic bases include lithium, sodium,potassium, magnesium, calcium and zinc. Salts derived from organic basesinclude ammonia, primary, secondary and tertiary amines, and aminoacids. Salts derived from inorganic acids include sulfuric,hydrochloric, phosphoric, hydrobromic. Salts derived from organic acidsinclude C₁₋₆ alkyl carboxylic acids, di-carboxylic acids andtricarboxylic acids such as acetic acid, proprionic acid, fumaric acid,maleic acid, succinic acid, tartaric acid, adipic acid and citric acid,and alkylsulfonic acids such as methanesulphonic, and aryl sulfonicacids such as para-tolouene sulfonic acid and benzene sulfonic acid.

Compounds in the disclosure may be in the form of a solvate. This occurswhen a compound of Formula (I) has an energetically favorableinteraction with a solvent, crystallizes in a manner that itincorporates solvent molecules into the crystal lattice or a complex isformed with solvent molecules in the solid or liquid state. Examples ofsolvents forming solvates are water (hydrates), MeOH, EtOH, iPrOH, andacetone.

Compounds in the disclosure may exist in different crystal forms knownas polymorphs. Polymorphism is the ability of a substance to exist intwo or more crystalline phases that have different arrangements and/orconformations of the molecule in the crystal lattice.

Compounds in the disclosure may exist as isotopically labeled compoundsof Formula (I) where one or more atoms are replaced by atoms having thesame atomic number but a different atomic mass from the atomic masswhich is predominantly seen in nature. Examples of isotopes include, butare not limited to hydrogen isotopes (deuterium, tritium), carbonisotopes (¹¹C, ¹³C, ¹⁴C) and nitrogen isotopes (¹³N, ¹⁵N). For example,substitution with heavier isotopes such as deuterium (²H) may offercertain therapeutic advantages resulting from greater metabolicstability which could be preferable and lead to longer in vivo half-lifeor dose reduction in a mammal or human.

Prodrugs of compounds embodied by Formula (I) are also within the scopeof this disclosure. Particular derivatives of compounds of Formula (I)which may have little to negligible pharmacological activity themselves,can, when administered to a mammal or human, be converted into compoundsof Formula (I) having the desired biological activity.

Compounds in the disclosure and their pharmaceutically acceptable salts,prodrugs, as well as metabolites of the compounds, may also be used totreat certain eating disorders, obesity, compulsive gambling, sexualdisorders, narcolepsy, sleep disorders, diabetes, metabolic syndrome,neurodegenerative disorders and CNS disorders/conditions as well as insmoking cessation treatment.

In one embodiment the treatment of CNS disorders and conditions by thecompounds of the disclosure can include Huntington's disease,schizophrenia and schizo-affective conditions, delusional disorders,drug-induced psychoses, panic and obsessive compulsive disorders,post-traumatic stress disorders, age-related cognitive decline,attention deficit/hyperactivity disorder, bipolar disorders, personalitydisorders of the paranoid type, personality disorders of the schizoidtype, psychosis induced by alcohol, amphetamines, phencyclidine, opioidshallucinogens or other drug-induced psychosis, dyskinesia or choreiformconditions including dyskinesia induced by dopamine agonists,dopaminergic therapies, psychosis associated with Parkinson's disease,psychotic symptoms associated with other neurodegenerative disordersincluding Alzheimer's disease, dystonic conditions such as idiopathicdystonia, drug-induced dystonia, torsion dystonia, and tardivedyskinesia, mood disorders including major depressive episodes,post-stroke depression, minor depressive disorder, premenstrualdysphoric disorder, dementia including but not limited to multi-infarctdementia, AIDS-related dementia, and neurodegenerative dementia.

In another embodiment, compounds of the disclosure may be used for thetreatment of eating disorders, obesity, compulsive gambling, sexualdisorders, narcolepsy, sleep disorders as well as in smoking cessationtreatment.

In a further embodiment, compounds of the disclosure may be used for thetreatment of obesity, schizophrenia, schizo-affective conditions,Huntington's disease, dystonic conditions and tardive dyskinesia.

In another embodiment, compounds of the disclosure may be used for thetreatment of schizophrenia, schizo-affective conditions, Huntington'sdisease and obesity.

In a further embodiment, compounds of the disclosure may be used for thetreatment of schizophrenia and schizo-affective conditions.

In an additional embodiment, compounds of the disclosure may be used forthe treatment of Huntington's disease.

In another embodiment, compounds of the disclosure may be used for thetreatment of obesity and metabolic syndrome.

Compounds of the disclosure may also be used in mammals and humans inconjuction with conventional antipsychotic medications including but notlimited to Clozapine, Olanzapine, Risperidone, Ziprasidone, Haloperidol,Aripiprazole, Sertindole and Quetiapine. The combination of a compoundof Formula (I) with a subtherapeutic dose of an aforementionedconventional antipsychotic medication may afford certain treatmentadvantages including improved side effect profiles and lower dosingrequirements.

DEFINITIONS

Alkyl is meant to denote a linear or branched saturated or unsaturatedaliphatic C₁-C₈ hydrocarbon which can be optionally substituted with upto 3 fluorine atoms and, if specified, substituted with other groups.Unsaturation in the form of a double or triple carbon-carbon bond may beinternal or terminally located and in the case of a double bond both cisand trans isomers are included. Examples of alkyl groups include but arenot limited to methyl, trifluoromethyl, ethyl, trifluoroethyl, isobutyl,neopentyl, cis- and trans-2-butenyl, isobutenyl, propargyl. C₁-C₄ alkylis the subset of alkyl limited to a total of up to 4 carbon atoms.

In each case in which a size range for the number of atoms in a ring orchain is disclosed, all subsets are disclosed. Thus, C_(x)-C_(y)includes all subsets, e.g., C₁-C₄ includes C₁-C₂, C₂-C₄, C₁-C₃ etc.

Acyl is an alkyl-C(O)— group wherein alkyl is as defined above. Examplesof acyl groups include acetyl and proprionyl.

Alkoxy is an alkyl-O— group wherein alkyl is as defined above. C₁-C₄alkoxy is the subset of alkyl-O— where the subset of alkyl is limited toa total of up to 4 carbon atoms. Examples of alkoxy groups includemethoxy, trifluoromethoxy, ethoxy, trifluoroethoxy, and propoxy.

Alkoxyalkyl is an alkyl-O—(C₁-C₄ alkyl)- group wherein alkyl is asdefined above. Examples of alkoxyalkyl groups include methoxymethyl andethoxymethyl.

Alkoxyalkyloxy is an alkoxy-alkyl-O— group wherein alkoxy and alkyl areas defined above. Examples of alkoxyalkyloxy groups includemethoxymethyloxy (CH₃OCH₂O—) and methoxyethyloxy (CH₃OCH₂CH₂O—) groups.

Alkylthio is alkyl-S— group wherein alkyl is as defined above. Alkylthioincludes C₁-C₄alkylathio.

Alkylsulfonyl is alkyl-SO₂— wherein alkyl is as defined above.Alkylsulfonyl includes C₁-C₄ alkylsulfonyl.

Alkylamino is alkyl-NH— wherein alkyl is as defined above. Alkylaminoincludes C₁-C₄ alkylamino.

Dialkylamino is (alkyl)₂-N— wherein alkyl is as defined above.

Amido is H₂NC(O)—.

Alkylamido is alkyl-NHC(O)— wherein alkyl is as defined above.

Dialkylamido is (alkyl)₂-NC(O)— wherein alkyl is as defined above.

Aromatic is heteroaryl or aryl wherein heteroaryl and aryl are asdefined below.

Aryl is a phenyl or napthyl group. Aryl groups may be optionally andindependently substituted with up to three groups selected from halogen,CF₃, CN, NO₂, OH, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy,alkoxyalkyl, aryloxy, alkoxyalkyloxy, heterocycloalkyl,heterocycloalkylalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy,—OCH₂CH₂OCH₃, —OC(O)R_(a), —OC(O)OR_(a), —OC(O)NHR_(a), —OC(O)N(R_(a)),—SR_(a), —S(O)R_(a), —NH₂, —NHR_(a), —N(R_(a))(R_(b)), —NHC(O)R_(a),—N(R_(a))C(O)R_(b), —NHC(O)OR_(a), —N(R_(a))C(O)OR_(b),—N(R_(a))C(O)NH(R_(b)), —N(R_(a))C(O)NH(R_(b))₂, —C(O)NH₂, —C(O)NHR_(a),—C(O)N(R_(a))(R_(b)), —CO₂H, —CO₂R_(a), —COR_(a) wherein R_(a) and R_(b)are independently chosen from alkyl, alkoxyalkyl, —CH₂CH₂OH, —CH₂CH₂OMe,cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, heterocycloalkyl, and heterocycloalkylalkyl, each ofwhich is optionally and independently substituted with up to threegroups selected from only halogen, Me, Et, ^(i)Pr, ^(t)Bu, unsubstitutedcyclopropyl, unsubstituted cyclobutyl, CN, NO₂, NH₂, CF₃, NHMe, NMe₂,OMe, OCF₃, each of which are attached via carbon-carbon orcarbon-nitrogen or carbon-oxygen single bonds; or R_(a) and R_(b) takentogether with the atom(s) to which they are attached form a 5-6 memberedring.

Arylalkyl is an aryl-alkyl- group wherein aryl and alkyl are as definedabove.

Aryloxy is an aryl-O— group wherein aryl is as defined above.

Arylalkoxy is an aryl-(C₁-C₄ alkyl)-O— group wherein aryl is as definedabove.

Carboxy is a CO₂H or CO₂R_(c) group wherein R_(c) is independentlychosen from, alkyl, C₁-C₄ alkyl, cycloalkyl, arylalkyl, cycloalkylalkyl,CF₃, and alkoxyalkyl, wherein alkyl is as defined above.

Cycloalkyl is a C₃-C₇ cyclic non-aromatic hydrocarbon which may containa single double bond and is optionally and independently substitutedwith up to three groups selected from alkyl, alkoxy, hydroxyl and oxo.Examples of cycloalkyl groups include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cyclopentenyl and cyclohexanonyl.

Cycloalkyloxy is a cycloalkyl-O— group wherein cycloalkyl is as definedabove. Examples include cyclopropyloxy, cyclobutyloxy andcyclopentyloxy. C₃-C₆ cycloalkyloxy is the subset of cycloalkyl-O— wherecycloalkyl contains 3-6 carbon atoms.

Cycloalkylalkyl is a cycloalkyl-(C₁-C₄ alkyl)- group. Examples includecyclopropylmethyl, cyclopropylethyl, cyclohexylmethyl andcyclohexylethyl.

Cycloalkylalkoxy is a cycloalkyl-(C₁-C₄ alkyl)-O— group whereincycloalkyl and alkyl are as defined above. Examples of cycloalkylalkoxygroups include cyclopropylmethoxy, cyclopentylmethoxy andcyclohexylmethoxy.

Halogen is F, Cl, Br or I.

Heteroaryl is a tetrazole, 1,2,3,4-oxatriazole, 1,2,3,5-oxatriazole, amono or bicyclic aromatic ring system, or a heterobicyclic ring systemwith one aromatic ring having 5 to 10 ring atoms independently selectedfrom C, N, O and S, provided that not more than 3 ring atoms in anysingle ring are other than C. Examples of heteroaryl groups include butare not limited to thiophenyl, furanyl, thiazolyl, isothiazolyl,oxazolyl, isoxazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, pyrrazolyl,imidazolyl, 1,2,3-triazolyl, 1,3,4-triazolyl, pyrimidinyl, pyrazinyl,indolyl, quinolyl, tetrahydroquinolyl, isoquinolyl,tetrahydroisoquinolyl, indazolyl, benzthiadiazololyl, benzoxadiazolyland benzimidazolyl. Heteroaryl groups may be optionally andindependently substituted with up to 3 substituents independentlyselected from halogen, CF₃, CN, NO₂, OH, alkyl, cycloalkyl,cycloalkylalkyl, alkoxy, alkoxyalkyl, aryloxy, alkoxyalkyloxy,heterocycloalkyl, heterocycloalkylalkyl, heterocycloalkyloxy,heteroaryl, heteroaryloxy, —OCH₂CH₂OCH₃, —OC(O)R_(a), —OC(O)OR_(a),—OC(O)NHR_(a), —OC(O)N(R_(a)), —SR_(a), —S(O)R_(a), —NH₂, —NHR_(a),—N(R_(a))(R_(b)), —NHC(O)R_(a), —N(R_(a))C(O)R_(b), —NHC(O)OR_(a),—N(R_(a))C(O)OR_(b), —N(R_(a))C(O)NH(R_(b)), —N(R_(a))C(O)NH(R_(b))₂,—C(O)NH₂, —C(O)NHR_(a), —C(O)N(R_(a))(R_(b)), —CO₂H, —CO₂R_(a), —COR_(a)wherein R_(a) and R_(b) are independently chosen from alkyl,alkoxyalkyl, —CH₂CH₂OH, —CH₂CH₂OMe, cycloalkyl, cycloalkylalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, andheterocycloalkylalkyl, each of which is optionally and independentlysubstituted with up to three groups selected from only halogen, Me, Et,^(i)Pr, ^(t)Bu, unsubstituted cyclopropyl, unsubstituted cyclobutyl, CN,NO₂, NH₂, CF₃, NHMe, NMe₂, OMe, OCF₃, each of which are attached viacarbon-carbon or carbon-nitrogen or carbon-oxygen single bonds; or R_(a)and R_(b) taken together with the atom(s) to which they are attachedform a 5-6 membered ring.

Heteroarylalkyl is a heteroaryl-(C₁-C₄ alkyl)- group wherein heteroaryland alkyl are as defined above. Examples of heteroarylalkyl groupsinclude 4-pyridinylmethyl and 4-pyridinylethyl.

Heteroaryloxy is a heteroaryl-O group wherein heteroaryl is as definedabove.

Heteroarylalkoxy is a heteroaryl-(C₁-C₄ alkyl)-O— group whereinheteroaryl and alkoxy are as defined above. Examples of heteroarylalkylgroups include 4-pyridinylmethoxy and 4-pyridinylethoxy.

Heterobicyclic ring system is a ring system having 8-10 atomsindependently selected from C, N, O and S, provided that not more than 3ring atoms in any single ring are other than carbon and provided that atleast one of the rings is aromatic; said bicyclic ring may be optionallyand independently substituted with up to 3 substituents independentlyselected from alkyl, alkoxy, cycloalkyl, C₃-C₆ cycloalkyloxy,cycloalkylalkyl, halogen, nitro, alkylsulfonyl and cyano. Examples of8-10 membered heterobicyclic ring systems include but are not limited to1,5-naphthyridyl, 1,2,3,4-tetrahydro-1,5-naphthyridyl 1,6-naphthyridyl,1,2,3,4-tetrahydro-1,6-naphthyridyl 1,7-naphthyridyl,1,2,3,4-tetrahydro-1,7-naphthyridinyl 1,8-naphthyridyl,1,2,3,4-tetrahydro-1,8-naphthyridyl, 2,6-naphthyridyl, 2,7-naphthyridyl,cinnolyl, isoquinolyl, tetrahydroisoquinolinyl, phthalazyl, quinazolyl,1,2,3,4-tetrahydroquinazolinyl, quinolyl, tetrahydroquinolinyl,quinoxalyl, tetrahydroquinoxalinyl, benzo[d][1,2,3]triazyl,benzo[e][1,2,4]triazyl, pyrido[2,3-b]pyrazyl, pyrido[2,3-c]pyridazyl,pyrido[2,3-d]pyrimidyl, pyrido[3,2-b]pyrazyl, pyrido[3,2-c]pyridazyl,pyrido[3,2-c]pyrimidyl, pyrido[3,4-b]pyrazyl, pyrido[3,4-c]pyridazyl,pyrido[3,4-d]pyrimidyl, pyrido[4,3-b]pyrazyl, pyrido[4,3-c]pyridazyl,pyrido[4,3-c]pyrimidyl, quinazolyl, 1H-benzo[d][1,2,3]triazoyl,1H-benzo[d]imidazoyl, 1H-indazoyl, 1H-indoyl,2H-benzo[d][1,2,3]triazoyl, 2H-pyrazolo[3,4-b]pyridinyl,2H-pyrazolo[4,3-b]pyridinyl, [1,2,3]triazolo[1,5-a]pyridinyl,[1,2,4]triazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl,benzo[b]thienyl, benzo[c][1,2,5]oxadiazyl, benzo[c][1,2,5]thiadiazolyl,benzo[d]isothiazoyl, benzo[d]isoxazoyl, benzo[d]oxazoyl,benzo[d]thiazoyl, benzofuryl, imidazo[1,2-a]pyrazyl,imidazo[1,2-a]pyridinyl, imidazo[1,2-a]pyrimidyl,imidazo[1,2-b]pyridazyl, imidazo[1,2-c]pyrimidyl, imidazo[1,5-a]pyrazyl,imidazo[1,5-a]pyridinyl, imidazo[1,5-a]pyrimidyl,imidazo[1,5-b]pyridazyl, imidazo[1,5-c]pyrimidyl, indolizyl,pyrazolo[1,5-a]pyrazyl, pyrazolo[1,5-a]pyridinyl,pyrazolo[1,5-a]pyrimidyl, pyrazolo[1,5-b]pyridazine,pyrazolo[1,5-c]pyrimidine, pyrrolo[1,2-a]pyrazine,pyrrolo[1,2-a]pyrimidyl, pyrrolo[1,2-b]pyridazyl,pyrrolo[1,2-c]pyrimidyl, 1H-imidazo[4,5-b]pyridinyl,1H-imidazo[4,5-c]pyridinyl, 1H-pyrazolo[3,4-b]pyridinyl,1H-pyrazolo[3,4-c]pyridinyl, 1H-pyrazolo[4,3-b]pyridinyl,1H-pyrazolo[4,3-c]pyridinyl, 1H-pyrrolo[2,3-b]pyridinyl,1H-pyrrolo[2,3-c]pyridinyl, 1H-pyrrolo[3,2-b]pyridinyl,1H-pyrrolo[3,2-c]pyridinyl, 2H-indazoyl, 3H-imidazo[4,5-b]pyridinyl,3H-imidazo[4,5-c]pyridinyl, benzo[c]isothiazyl, benzo[c]isoxazyl,furo[2,3-b]pyridinyl, furo[2,3-c]pyridinyl, furo[3,2-b]pyridinyl,furo[3,2-c]pyridinyl, isothiazolo[4,5-b]pyridinyl,isothiazolo[4,5-c]pyridinyl, isothiazolo[5,4-b]pyridinyl,isothiazolo[5,4-c]pyridinyl, isoxazolo[4,5-b]pyridinyl,isoxazolo[4,5-c]pyridinyl, isoxazolo[5,4-b]pyridinyl,isoxazolo[5,4-c]pyridinyl, oxazolo[4,5-b]pyridinyl,oxazolo[4,5-c]pyridinyl, oxazolo[5,4-b]pyridinyl,oxazolo[5,4-c]pyridinyl, thiazolo[4,5-b]pyridiyl,thiazolo[4,5-c]pyridinyl, thiazolo[5,4-b]pyridinyl,thiazolo[5,4-c]pyridinyl, thieno[2,3-b]pyridinyl,thieno[2,3-c]pyridinyl, thieno[3,2-b]pyridinyl andthieno[3,2-c]pyridinyl.

Heterocycloalkyl is a non-aromatic, monocyclic or bicyclic saturated orpartially unsaturated ring system comprising 5-10 ring atoms selectedfrom C, N, O and S, provided that not more than 2 ring atoms in anysingle ring are other than C. In the case where the heterocycloalkylgroup contains a nitrogen atom the nitrogen may be substituted with analkyl, acyl, —C(O)O-alkyl, —C(O)NH(alkyl) or a —C(O)N(alkyl)₂ group.Heterocycloalkyl groups may be optionally and independently substitutedwith hydroxy, alkyl and alkoxy groups and may contain up to two oxogroups. Heterocycloalkyl groups may be linked to the rest of themolecule via either carbon or nitrogen ring atoms. Examples ofheterocycloalkyl groups include tetrahydrofuranyl, tetrahydrothienyl,tetrahydro-2H-pyran, tetrahydro-2H-thiopyranyl, pyrrolidinyl,pyrrolidonyl, succinimidyl, piperidinyl, piperazinyl,N-methylpiperazinyl, morpholinyl, morpholin-3-one, thiomorpholinyl,thiomorpholin-3-one, 2,5-diazabicyclo[2.2.2]octanyl,2,5-diazabicyclo[2.2.1]heptanyl, octahydro-1H-pyrido[1,2-a]pyrazine,3-thia-6-azabicyclo[3.1.1]heptane and 3-oxa-6-azabicyclo[3.1.1]heptanyl.

Heterocycloalkylalkyl is a heterocycloalkyl-(C₁-C₄ alkyl)- group whereinheterocycloalkyl is as defined above.

Heterocycloalkyloxy is a heterocycloalkyl-O— group whereinheterocycloalkyl is as defined above.

Heterocycloalkylalkoxy is a heterocycloalkyl-(C₁-C₄ alkyl)-O— groupwherein heterocycloalkyl is as defined above.

Oxo is a —C(O)— group.

Phenyl is a benzene ring which may be optionally and independentlysubstituted with up to three groups selected from halogen, CF₃, CN, NO₂,OH, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl, aryloxy,alkoxyalkyloxy, heterocycloalkyl, heterocycloalkylalkyl,heterocycloalkyloxy, heteroaryl, heteroaryloxy, —OCH₂CH₂OCH₃,—OC(O)R_(a), —OC(O)OR_(a), —OC(O)NHR_(a), —OC(O)N(R_(a)), —SR_(a),—S(O)R_(a), —NH₂, —NHR_(a), —N(R_(a))(R_(b)), —NHC(O)R_(a),—N(R_(a))C(O)R_(b), —NHC(O)OR_(a), —N(R_(a))C(O)OR_(b),—N(R_(a))C(O)NH(R_(b)), —N(R_(a))C(O)NH(R_(b))₂, —C(O)NH₂, —C(O)NHR_(a),—C(O)N(R_(a))(R_(b)), —CO₂H, —CO₂R_(a), —COR_(a) wherein R_(a) and R_(b)are independently chosen from alkyl, alkoxyalkyl, —CH₂CH₂OH, —CH₂CH₂OMe,cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, heterocycloalkyl, and heterocycloalkylalkyl, each ofwhich is optionally and independently substituted with up to threegroups selected from only halogen, Me, Et, ^(i)Pr, ^(t)Bu, unsubstitutedcyclopropyl, unsubstituted cyclobutyl, CN, NO₂, NH₂, CF₃, NHMe, NMe₂,OMe, OCF₃, each of which are attached via carbon-carbon orcarbon-nitrogen or carbon-oxygen single bonds; or R_(a) and R_(b) takentogether with the atom(s) to which they are attached form a 5-6 memberedring.

Restricted phenyl is a benzene ring which may be optionally andindependently substituted with up to three groups selected from halogen,CF₃, CN, alkoxy, alkoxyalkyl, aryloxy, alkoxyalkyloxy, heterocycloalkyl,heterocycloalkyloxy, heteroaryl, heteroaryloxy, —OCH₂CH₂OCH₃,—OC(O)R_(a), —OC(O)OR_(a), —OC(O)N(R_(a)), —N(R_(a))(R_(b)),—NHC(O)R_(a), —N(R_(a))C(O)R_(b), —NHC(O)OR_(a), —N(R_(a))C(O)OR_(b),—C(O)N(R_(a))(R_(b)), —COR_(a) wherein R_(a) and R_(b) are independentlychosen from alkyl, alkoxyalkyl, —CH₂CH₂OH, —CH₂CH₂OMe, cycloalkyl,cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,heterocycloalkyl, and heterocycloalkylalkyl, each of which is optionallyand independently substituted with up to three groups selected from onlyhalogen, Me, Et, ^(i)Pr, ^(t)Bu, unsubstituted cyclopropyl,unsubstituted cyclobutyl, CN, NO₂, NH₂, CF₃, NHMe, NMe₂, OMe, OCF₃, eachof which are attached via carbon-carbon or carbon-nitrogen orcarbon-oxygen single bonds; or R_(a) and R_(b) taken together with theatom(s) to which they are attached form a 5-6 membered ring.

Abbreviations used in the following examples and preparations include:

-   -   Ac Acyl (Me-C(O)—)    -   AcN Acetonitrile    -   BINAP 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl    -   Bn Benzyl    -   Celite® Diatomaceous earth    -   DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene    -   DCC N,N′, Dicyclohexylcarbodiimide    -   DCM Dichloromethane    -   DIEA Di-isopropylethyl amine    -   DIPEA Di-isopropylethyl amine    -   DMAP 4-Dimethylaminopyridine    -   DMF Dimethylformamide    -   DMP Dess Martin Periodinane    -   DMSO Dimethyl sulfoxide    -   Dppf 1,4-Bis(diphenylphosphino) ferrocene    -   EDC 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide Hydrochloride    -   Et₃N Triethylamine    -   g gram(s)    -   h Hour(s)    -   hr Hour(s)    -   HATU 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium        hexafluorophosphate    -   HMDS Hexamethyldisilazide    -   HOBt 1-Hydroxybenzotriazole    -   HPLC High Pressure Liquid Chromatography    -   HRMS High resolution mass spectrometry    -   i.v. Intravenous    -   KHMDS Potassium Hexamethydisilazide    -   LDA Lithium Di-isopropylamide    -   m Multiplet    -   m- meta    -   MEM Methoxyethoxymethyl    -   MeOH Methyl Alcohol or Methanol    -   min Minute(s)    -   mmol millimoles    -   mmole millimoles    -   Ms Mesylate    -   MS Mass Spectrometry    -   MW Molecular Weight    -   NBS N-Bromosuccinamide    -   NIS N-Iodosuccinamide    -   NMR Nuclear Magnetic Resonance    -   NMM N-Methyl Morpholine    -   NMP N-Methyl-2-pyrrolidone    -   o ortho    -   o/n overnight    -   p para    -   PCC Pyridinium Chlorochromate    -   PEPPSI        1,3-Bis(2,6-diisopropylphenyl)imidazolidene)(3-chloropyridinyl)        palladium(II)dichloride    -   PhNTf₂        1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide    -   POPd Dihydrogen dichlorobis(di-tert-butylphosphinito-kp)        palladate (2-)    -   p.s.i. Pounds per square inch    -   PPA Polyphosphoric acid    -   PPAA 1-Propanephosphonic Acid Cyclic Anhydride    -   PTSA p-Toluenesulfonic acid    -   PyBOP® Benzotriazol-1-yl-oxytripyrrolidinophosphonium        hexafluorophosphate    -   RT (or rt) room temperature (about 20-25° C.)    -   s Singlet    -   sat. Saturated    -   t Triplet    -   TBAF Tetra-butyl ammonium fluoride    -   TEA Triethylamine    -   TFA Trifluoroacetic Acid    -   THF Tetrahydrofuran    -   TLC Thin layer chromatography    -   TMS Trimethylsilyl    -   Tf Triflate    -   Tof-MS Time of Flight Mass Spectrometry    -   Ts Tosylate    -   v/v volume/volume    -   wt/v weight/volume

DETAILED DESCRIPTION

The 1,2 disubstituted heterocyclic compounds of Formula I may beprepared from multi-step organic synthesis routes from commerciallyavailable starting materials by one skilled in the art of organicsynthesis using established organic synthetic procedures.Non-commercially available phenyl acetic acids can be made fromcommercially available starting materials via methods known by oneskilled in the art of organic synthesis. Such methods include synthesisfrom the corresponding aryl acids via. the Wolff rearrangement usingdiazomethane.

Compounds of the disclosure where HET is A29 and A31 may be preparedgenerally as depicted in Schemes 1-8 below.

Compounds of the disclosure of Formula (I) wherein HET is A29 andX=phenyl or heteroaryl (each respectively optionally substituted) thushaving general Formula LIV may be prepared generally as depicted inScheme 1:

Alternatively, compounds of the disclosure of Formula (I) wherein HET isA29 and X=phenyl or heteroaryl (each respectively optionallysubstituted) and thus having general Formula LIV may also be preparedgenerally as depicted in Scheme 2:

Intermediate compounds of Formula LXIII may alternatively be synthesizedas depicted in Scheme 3.

Compounds of the disclosure of Formula (I) wherein HET is A31 andX=phenyl or heteroaryl (each optionally substituted) are as describedpreviously and thus having general Formula LXXIV may be preparedgenerally as depicted in Scheme 4:

The general synthesis of heterocyclic chloride intermediates (Z—CH₂—Cl)where Z corresponds to an imidazo[1,2-a]pyrid-2-yl is depicted in Scheme5.

The general synthesis of heterocyclic chloride intermediates (Z—CH₂—Cl)where Z corresponds to an imidazo[1,2-b]pyridazin-6-yl is depicted inScheme 6.

The general synthesis of heterocyclic chloride intermediates (Z—CH₂—Cl)where Z corresponds to an imidazo[1,2-b]pyridazin-2-yl is depicted inScheme 7.

The general synthesis of heterocyclic chloride intermediates (Z—CH₂—Cl)where Z corresponds to either a 5-substituted-pyridin-2-yl or a3,5-disubstituted-1pyridin-2-yl is depicted in Scheme 8.

Reactive groups not involved in the above processes can be protectedwith standard protecting groups during the reactions and removed bystandard procedures (T. W. Greene & P. G. M. Wuts, Protecting Groups inOrganic Synthesis, Third Edition, Wiley-Interscience) known to those ofordinary skill in the art. Presently preferred protecting groups includemethyl, benzyl, MEM, acetate and tetrahydropyranyl for the hydroxylmoiety, and BOC, Cbz, trifluoroacetamide and benzyl for the aminomoiety, methyl, ethyl, tert-butyl and benzyl esters for the carboxylicacid moiety. Practitoners in the art will also recognize that the orderof certain chemical reactions can be changed. Practitioners of the artwill also note that alternative reagents and conditions exist forvarious chemical steps.

Experimental Procedures

The synthesis of N-methoxy-N-methylcarboxamides from their correspondingcarboxylic acids is known by those of ordinary skill in the art. Arepresentative procedure is described below, where is selected from

To a stirred solution of carboxylic acid (1 eq., 3 mmol) in DCM (50 mL)was added HATU (1.5 eq, 4.5 mmol), N-methoxy methylamine (1.5 eq, 4.5mmol) and TEA (3 eq., 9 mmol) at RT under nitrogen atmosphere. Thereaction mixture was then stirred at RT for 3 h. The reaction mixturewas diluted with water and the aqueous layer was extracted with DCM(3×50 mL). The combined organic extracts were washed with water (50 mL),brine (20 mL), dried over anhydrous Na₂SO₄, filtered and evaporatedunder reduced pressure to afford the correspondingN-methoxy-N-methylcarboxamide.

HPLC Conditions

Condition-A:

Column: Acquity BEH C-18 (50×2.1 mm, 1.7μ,)

Column Temp: 25° C.

Mobile Phase A/B: Acetonitrile (0.025% TFA) and water

Flow Rate: 0.50 mL/Min

4-(5,5-dimethyl-4-oxo-4,5-dihydrofuran-2-yl)benzonitrile

To a suspension of NaH (0.9 g) in THF at RT was added3-hydroxy-3-methyl-2-butanone (1 g) and ethyl methyl 4-cyanobenzoate(1.58 g). The resultant mixture was refluxed overnight, upon which thereaction was quenched with 12N HCl (6 mL). MgSO4 (excess) was addeduntil the organic phase became clear. The solids were removed byfiltration and the filtrate was concentrated under reduced pressure. Theresidue was purified by column chromatography to give4-(5,5-dimethyl-4-oxo-4,5-dihydrofuran-2-yl)benzonitrile (0.63 g).

Synthesis of4-(4-Hydroxyphenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one4-Methoxy-N-methoxy-N-methylbenzamide

To a stirred solution of 4-methoxybenzoic acid (10.0 g, 65.70 mmol) inDCM (50 mL) were added EDCI (18.90 g, 98.60 mmol), HOBT (10.0 g, 65.70mmol), N-methoxy methylamine (13.0 g, 131.40 mmol) and DIPEA (34.3 mL,197.20 mmol) at RT under a nitrogen atmosphere. The reaction mixture wasstirred at RT for 12 h. The reaction mixture was diluted with water andthe aqueous layer was extracted with DCM (3×100 mL). The combinedorganic extracts were washed with water (2×100 mL), brine (2×50 mL),dried over anhydrous Na₂SO₄, filtered and evaporated under reducedpressure to afford crude product. The crude material was purified byflash column chromatography using 20% ethyl acetate in hexane and silicagel (230-400 Mesh) to afford N,4-dimethoxy-N-methylbenzamide (11.0 g,86%) as a colorless liquid.

4-Hydroxy-1-(4-methoxyphenyl)-4-methylpent-2-yn-1-one

To a stirred solution of 2-methylbut-3-yn-2-ol (2.15 g, 25.6 mmol) indry THF (80 mL) was added n-BuLi (24.0 mL, 38.7 mmol, 1.6 M in hexane)drop wise at −20° C. under an inert atmosphere for a period of 10 min.After being stirred for 30 min at −20° C., a solution ofN,4-dimethoxy-N-methylbenzamide (2.5 g, 12.8 mmol) in dry THF (10 mL)was added to reaction mixture and stirring was continued for anadditional 3 h at −20° C. The reaction mixture was quenched with asaturated NH₄Cl solution and extracted with EtOAc (2×100 mL). Thecombined organic layer was washed with water (100 mL), brine (40 mL),dried over Na₂SO₄, filtered and concentrated in vacuo to afford4-hydroxy-1-(4-methoxyphenyl)-4-methylpent-2-yn-1-one (2.25 g, 81%) as acolorless liquid.

5-(4-Methoxyphenyl)-2,2-dimethylfuran-3(2H)-one

To 4-hydroxy-1-(4-methoxyphenyl)-4-methylpent-2-yn-1-one (10 g, 45.8mmol) was added methanolic ammonia (50 mL) at room temperature and thereaction mixture was stirred overnight. The mixture was concentratedunder reduced pressure and 50% aqueous acetic acid was added. Theresultant mixture was heated at reflux for 4 hours. The pH was adjustedto 8 with saturated ammonium chloride solution and extracted with DCM.The combined organics were washed with water and brine solution, driedover sodium sulphate, filtered, concentrated under reduced pressure andwashed with heptane to afford5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (8.6 g, 86%) as whitesolid. ¹H NMR (500 MHz, d₆-DMSO): δ 7.99 (d, 2H), 7.15 (d, 2H), 6.20 (s,1H), 3.89 (s, 3H). 1.42 (s, 6H). MS: [M+H]+: m/z=218.1.

4-Bromo-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one

To a stirred solution of 5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one(5.5 g, 0.025 mol) in CHCl₃ (100 mL) was added NBS (6.733 g, 0.038 mol)portion wise at RT. The reaction mixture was stirred for 2 h at RT. Thereaction mixture was diluted with DCM (100 mL), washed with water (50mL), brine (50 mL), dried over Na₂SO₄, filtered and then concentrated invacuo to obtain the crude product. The crude material was purified viaby flash column chromatography using 25% ethyl acetate in hexane andsilica gel (230-400 Mesh) to afford4-bromo-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (4.6 g, 65%) asa solid.

4-(4-(Benzyloxy)phenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one

4-Bromo-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (2 g, 6.7 mol),2-(4-(benzyloxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.43 g,0.0067 mol), and Cs₂CO₃ (11 g, 0.034 mol) in toluene (25 mL) and water(8 mL) was degassed, Pd (dppf) Cl₂ (1.1 g, 0.0013 mol) was added underan inert atmosphere and the mixture degassed once again. The reactionwas heated at reflux for 3 h, upon which the reaction mixture wasfiltered through a pad of Celite® and the filtrate was diluted withEtOAc (100 mL), washed with water (50 mL), brine (50 mL), dried overNa₂SO₄, filtered and concentrated in vacuo to obtain the crude product.The crude material was purified by flash column chromatography using 30%ethyl acetate in hexane and silica gel (230-400 Mesh), Rf=0.30 to afford4-(4-(benzyloxy)phenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one(2.3 g, 73%) as solid. ¹H NMR (500 MHz, d₆-DMSO): δ 8.42 (d, J=7.6 Hz,1H), 8.06-7.99 (m, 2H), 7.95 (t, J=7.2 Hz, 1H), 7.72 (t, J=7.2 Hz, 1H),7.63 (t, J=7.8 Hz, 1H), 7.56 (d, J=7.2 Hz, 2H); 7.18 (d, J=7.4 Hz, 2H),7.12 (d, J=7.2 Hz, 2H), 6.89 (d, J=7.2 Hz, 2H), 5.38 (s, 2H), 3.79 (s,3H). 1.42 (s, 6H). MS: [M+H]+: m/z=452.1; [M+Na]+: m/z=474.2.

4-(4-Hydroxyphenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one

5% Palladium on carbon (7.0 g) was added to a solution4-(4-(benzyloxy)phenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one(19 g, 42.1 mmol) in methanol (25 ml) at RT under an atmosphere ofnitrogen. The nitrogen atmosphere was changed to an atmosphere ofhydrogen. The reaction mixture was stirred under an atmosphere ofhydrogen at RT for 4 h (the reaction was monitored by TLC). The reactionmixtures was filtered over through a pad of Celite®, washed withmethanol, concentrated in vacuo and the resultant residue was slurriedwith heptane. The solid was filtered & dried under vacuum to afford4-(4-hydroxyphenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one(14.0 g, 95%,) as light yellow solid. ¹H NMR, 500 MHz, DMSO-d₆: δ 9.5(bs, 1H), 7.55 (d, 2H), 7.05 (d, 2H), 7.0 (d, 2H), 6.75 (d, 2H), 3.8 (s,3H), 1.4 (s, 6H). MS: [M+H]: m/z=311.2. HPLC: (98.8%, Eclipse XDB-C18,150×4.6 mm, 5 um. Mobile Phase: 0.1% TFA in Water. (A). ACN (B), Flowrate: 1.5 ml/min).

Synthesis of5-(4-Hydroxyphenyl)-2,2-dimethyl-4-(pyridin-4-yl)furan-3(2H)-oneTrimethyl (2-methylbut-3-yn-2-yloxy) silane

To a stirred solution of 2-methylbut-3-yn-2-ol (20 g, 0.23 mol) in HMDS(42.3 g, 0.261 mol) was added LiClO₄ (38.03 g, 0.35 mol) at RT. Thereaction mixture was then stirred for additional 30 minutes, dilutedwith water (100 mL) and then extracted with ether (3×200 mL). Thecombined ether layers were washed with water (100 mL) and brine (100mL), dried over Na₂SO and filtered. The ether was distilled off at 80°C. to afford trimethyl (2-methylbut-3-yn-2-yloxy) silane (25 g) as anoil.

4-Methyl-1-(pyridin-4-yl)-4-(trimethylsilyloxy)pent-2-yn-1-one

To a pre-cooled −78° C. stirred solution of trimethyl(2-methylbut-3-yn-2-yloxy) silane (5.0 g, 0.03 mol) in dry THF (150 mL),n-BuLi (23.82 mL, 0.03 mol, 1.6 M in hexane) was added dropwise over aperiod of 10 minutes under an inert atmosphere. The reactions wasstirred for 30 minutes at −78° C. and then a solution ofN-methoxy-N-methylisonicotinamide (6.34 g, 0.03 mol) in dry THF (30 mL)was added to the reaction mixture and stirring was continued for anadditional 40 min at −78° C. The reaction mixture was quenched with asaturated NH₄Cl solution and extracted with EtOAc (2×100 mL). Thecombined organic layers were washed with water (100 mL) and brine (100mL), dried over Na₂SO₄, filtered and finally concentrated in vacuo toobtain a residue. The residue was purified via silica gel columnchromatography eluting with 5% EtOAc in hexanes to afford4-methyl-1-(pyridin-4-yl)-4-(trimethylsilyloxy)pent-2-yn-1-one (2.2 g,27%) as oil.

4-Hydroxy-4-methyl-1-(pyridin-4-yl) pent-2-yn-1-one

To a stirred solution of 4-methyl-1-(pyridin-4-yl)-4-(trimethylsilyloxy)pent-2-yn-1-one (0.5 g, 1.915 mmol) in DCM (10 mL) was added PTSA (0.47g, 2.49 mmol) at RT and the reaction mixture was stirred for 2 h. Thereaction mixture was diluted with DCM (50 mL). The organic layers werewashed with a saturated NaHCO₃ solution and water, dried over Na₂SO₄,filtered and then concentrated in vacuo to afford4-hydroxy-4-methyl-1-(pyridin-4-yl) pent-2-yn-1-one (0.35 g, 96%) as anoil.

2,2-Dimethyl-5-(pyridin-4-yl)furan-3(2H)-one

To a stirred solution of 4-hydroxy-4-methyl-1-(pyridin-4-yl)pent-2-yn-1-one (1.49 g, 0.007 mol) in ethanol (15 mL), diethylamine(0.511 g, 0.007 mol) in EtOH (15 mL) was added dropwise at RT. Themixture was then stirred for additional 40 min. The EtOH was evaporatedand the mixture was diluted with EtOAc (100 mL). The organic layers werewashed with water (50 mL) and brine (20 mL), dried over Na₂SO₄, filteredand concentrated in vacuo to afford2,2-dimethyl-5-(pyridin-4-yl)furan-3(2H)-one (1.4 g).

4-Bromo-2,2-dimethyl-5-(pyridin-4-yl)furan-3(2H)-one

To a stirred solution of 2,2-dimethyl-5-(pyridin-4-yl)furan-3(2H)-one(0.81 g, 4.28 mmol) in CHCl₃ (20 mL), NBS (1.3 g, 7.28 mmol) was addedportionwise at RT. The reaction mixture was then stirred for 2 h anddiluted with DCM (100 mL). The organic layers were washed with water (50mL) and brine (50 mL), dried over Na₂SO₄, filtered, and thenconcentrated in vacuo to obtain the crude product. The crude materialwas purified via silica gel column chromatography to afford4-bromo-2,2-dimethyl-5-(pyridin-4-yl)furan-3(2H)-one (0.25 g, 21%) as asolid.

4-(4-(Benzyloxy)phenyl)-2,2-dimethyl-5-(pyridin-4-yl)furan-3(2H)-one

A solution of 4-bromo-2,2-dimethyl-5-(pyridin-4-yl)furan-3(2H)-one (10.0g, 37.2 mmol),2-(4-(benzyloxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (13.8 g,44.7 mmol), and Cs₂CO₃ (36.27 g, 111.6 mmol) in toluene (100 mL) andwater (50 mL) was degassed.Dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(ll) (2.7 g, 3.7mmol) was added under an inert atmosphere and again degassed. Then thereaction was refluxed for 3 h and monitored by TLC. Upon completeconsumption of the starting material, the reaction mixture was filteredthrough a bed of Celite® washing with ethyl acetate. The organic layerwas then washed with water, brine, dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography using 20% ethyl acetate in n-hexanes on 230-400mesh silica gel to afford4-(4-(benzyloxy)phenyl)-2,2-dimethyl-5-(pyridin-4-yl)furan-3(2H)-one(8.3 g, 60.2%) as a light orange color solid. ¹H NMR, 500 MHz, DMSO-d₆:δ 8.2 (d, 2H), 7.85 (d, 2H), 7.6 (d, 4H), 7.4 (t, 1H), 7.15 (d, 2H),7.05 (d, 2H), 5.1 (s, 2H), 1.45 (s, 6H). MS: [M+H]+: m/z=396.0. HPLC:(97.5%, Column: Eclipse XDB-C18, 150×4.6 mm, 5 um. Mobile Phase: 0.1%TFA in Water. (A). ACN (B), Flow rate: 1.5 ml/min).

5-(4-Hydroxyphenyl)-2,2-dimethyl-4-(pyridin-4-yl)furan-3(2H)-one

To a stirred solution of5-(4-(benzyloxy)phenyl)-2,2-dimethyl-4-(pyridin-4-yl)furan-3(2H)-one(620 mg, 0.001 mmol) in MeOH (15 mL) was added Pd (OH)₂ (120 mg, 0.85mmol) at RT under an inert atmosphere. The reaction mixture was stirredunder a hydrogen atmosphere for 1 h. The reaction mixture was thenfiltered through a pad of Celite® and the filtrate was concentrated invacuo to obtain the crude product. The crude material was purified viasilica gel column chromatography to afford544-hydroxyphenyl)-2,2-dimethyl-4-(pyridin-4-yl)furan-3(2H)-one (280 mg,60%) as a solid.

Synthesis of4-(3-(4-Hydroxyphenyl)-5,5-dimethyl-4-oxo-4,5-dihydrofuran-2-yl)benzonitrile4-Cyano-N-methoxy-N-methylbenzamide

To a stirred solution of 4-cyanobenzoic acid (5.0 g, 34.0 mmol) in DCM(75 mL) were added HATU (19.40 g, 51.0 mmol), N-methoxy, N-methylamine(4.90 g, 51.0 mmol) and TEA (14.30 mL, 102.0 mmol) at RT under anitrogen atmosphere. The reaction mixture was then stirred at RT for 3h, diluted with water and the aqueous layer was extracted with DCM(3×100 mL). The combined organic extracts were washed with water (60 mL)and brine (30 mL), dried over anhydrous Na₂SO₄, filtered and evaporatedunder reduced pressure to afford 4-cyano-N-methoxy-N-methylbenzamide(6.2 g, 96%) as a yellow color oil.

4-(4-Methyl-4-(trimethylsilyloxy)pent-2-ynoyl)benzonitrile

To a −78° C. stirred solution of trimethyl (2-methylbut-3-yn-2-yloxy)silane (3.3 g, 20.00 mmol) in dry THF (45 mL), n-BuLi (4.1 mL, 9.00mmol, 1.6 M in hexane) was added dropwise over 10 minutes under an inertatmosphere. The reaction mixture was stirred for 30 min at −78° C., andthen a solution of 4-cyano-N-methoxy-N-methylbenzamide (2.0 g, 10.00mmol) in dry THF (15 mL) was added to the reaction mixture and stirringwas continued for an additional 1 h at −78° C. The reaction mixture wasquenched with a saturated NH₄Cl solution and extracted with EtOAc (2×100mL). The combined organic layers were washed with water (50 mL) andbrine (50 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo toobtain the crude product. The crude material was purified via silica gelcolumn chromatography eluting with 15% EtOAc in hexanes to afford4-(4-methyl-4-(trimethylsilyloxy)pent-2-ynoyl)benzonitrile (3.8 g, 68%)as a yellow oil.

4-(4-Hydroxy-4-methylpent-2-ynoyl)benzonitrile

To a stirred solution of4-(4-methyl-4-(trimethylsilyloxy)pent-2-ynoyl)benzonitrile (1.7 g, 5.00mmol) in DCM (15 mL) was added PTSA (1.70 g, 8.90 mmol) at RT and thereaction mixture was stirred for 30 min. The reaction mixture wasdiluted with water (10 mL) and extracted with DCM (2×50 mL). Thecombined organic layers were washed with a saturated NaHCO₃ solution andwater, dried over Na₂SO₄, filtered, and then concentrated in vacuo toafford 4-(4-hydroxy-4-methylpent-2-ynoyl)benzonitrile (1.20 g) as ayellow oil.

4-(5,5-Dimethyl-4-oxo-4,5-dihydrofuran-2-yl)benzonitrile

To a stirred solution of crude4-(4-hydroxy-4-methylpent-2-ynoyl)benzonitrile (1.2 g, 5.60 mmol) inethanol (12 mL), a solution of diethyl amine (0.58 mL, 5.60 mmol) inEtOH (5 mL) was added dropwise at RT. The reaction mixture was thenstirred for additional 1 h. The ethanol was removed and the mixture thendiluted with EtOAc (50 mL). The combined organic layers were washed withwater (10 mL), brine (10 mL), dried over Na₂SO₄, filtered, andconcentrated in vacuo to afford crude4-(5,5-dimethyl-4-oxo-4,5-dihydrofuran-2-yl)benzonitrile (1.2 g) as alight green semi solid which was taken on to the next step withoutfurther purification.

4-(3-Bromo-5,5-dimethyl-4-oxo-4,5-dihydrofuran-2-yl)benzonitrile

To a stirred solution of4-(5,5-dimethyl-4-oxo-4,5-dihydrofuran-2-yl)benzonitrile (1.2 g, 5.60mmol) in CHCl₃ (12 mL), NBS (1.1 g, 6.00 mmol) was added portionwise atRT. The reaction mixture was then stirred for 3 h and diluted with DCM(100 mL). The combined organic layers were washed with water (30 mL) andbrine (30 mL), dried over Na₂SO₄, filtered, and then concentrated invacuo to obtain the crude product. The crude material was purified viasilica gel column chromatography to afford4-(3-bromo-5,5-dimethyl-4-oxo-4,5-dihydrofuran-2-yl)benzonitrile (0.50g, 31%) as an off white solid.

4-(3-(4-(benzyloxy)phenyl)-5,5-dimethyl-4-oxo-4,5-dihydrofuran-2-yl)benzonitrile

A solution of4-(3-bromo-5,5-dimethyl-4-oxo-4,5-dihydrofuran-2-yl)benzonitrile (29.0g, 107.4 mmol),2-(4-(benzyloxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (34.7 g,118.8 mmol), and Cs₂CO₃ (104.7 g, 322.2 mmol) in toluene (200 mL) andwater (50 mL) was degassed.Dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) (8.5 g, 10mmol) was added under an inert atmosphere and the solution was againdegassed. The reaction was then refluxed for 3 h and monitored forcompletion by TLC. Upon complete consumption of the starting material,the reaction mixture was filtered through a bed of Celite® washing withethyl acetate. The organic layer was then washed with water, brine,dried over Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by flash column chromatography using 20% ethylacetate in n-hexane on 230-400 mesh silica gel (Rf=0.3) to afford4-(3-(4-(benzyloxy)phenyl)-5,5-dimethyl-4-oxo-4,5-dihydrofuran-2-yl)benzonitrile(31.5 g, 74.25%) as solid. ¹H NMR: 500 MHz, DMSO-d₆: δ 7.95 (d, 2H),7.75 (d, 2H), 7.5 (d, 4H), 7.35 (t, 1H), 7.15 (d, 2H), 7.05 (d, 2H), 5.1(s, 2H), 1.45 (s, 6H). MS: [M+H]+: m/z=396.0. HPLC: (99.5%, EclipseXDB-C18, 150×4.6 mm, 5 um. Mobile Phase: 0.1% TFA in Water. (A). ACN(B), Flow rate: 1.5 ml/min).

4-(3-(4-Hydroxyphenyl)-5,5-dimethyl-4-oxo-4,5-dihydrofuran-2-yl)benzonitrile

Boron tribromide (3.4 g, 15.8 mmol) was added to a solution of4-(3-(4-(benzyloxy)phenyl)-5,5-dimethyl-4-oxo-4,5-dihydrofuran-2-yl)benzonitrile(2.5 g, 6.3 mmol) in DCM at 0° C. & the mixture was stirred for 1 h(reaction was monitored by TLC). Upon complete consumption of thestarting material, the mixture was quenched with chilled water andextracted with DCM, The combined organics were dried over sodiumsulfate, filtered and concentrated under reduced pressure. The residuewas purified by column chromatography to afford4-(3-(4-hydroxyphenyl)-5,5-dimethyl-4-oxo-4,5-dihydrofuran-2-yl)benzonitrile(1.8 g, 93.2%,) as yellow solid. ¹H NMR: 500 MHz, CDCl₃: δ 9.6 (s, 1H),7.95 (d, 2H), 7.75 (d, 2H), 7.0 (d, 2H), 6.75 (d, 2H), 1.5 (s, 6H).

2,3,5-Trimethylpyridine 1-oxide

3-Chloro per benzoic acid (10 g, 164.2 mmol) was added to a solution of2,3,5-trimethylpyridine (10 g, 82.1 mmol) in DCM at 0° C. and themixture was stirred at RT for 8 h (the reaction was monitored by TLC).The reaction was quenched with sodium bicarbonate solution and stirredfor 1 h at RT. The organic layer was separated, dried over sodiumsulfate, filtered and concentrated under reduced pressure to afford2,3,5-trimethylpyridine 1-oxide (6.5 g, 58.0%,) as a brown solid. ¹HNMR: 200 MHz, CDCl₃: δ 8.15 (s, 1H), 7.15 (s, 1H), 2.55 (s, 3H), 2.35(s, 3H), 2.25 (s, 3H). MS: [M+H]+: m/z=311.2.

2-(Chloromethyl)-3,5-dimethylpyridine

Tosyl chloride (12.5 g, 65.6 mmol) was added to a solution of2,3,5-trimethylpyridine 1-oxide (6.0 g, 43.7 mmol), and triethylamine(6.6 g, 65.6 mmol) in DCM (60 ml) at RT under an atmosphere of nitrogen.The reaction mixture was heated to reflux and reflux was maintained 4 h(reaction was monitored by TLC). The reaction was quenched with waterand extracted with DCM. The combined organics were dried over sodiumsulfate, filtered and concentrated under reduced pressure. The residuewas purified by flash column chromatography using 10% ethyl acetate inn-hexanes and silica gel (230-400 Mesh) to afford2-(chloromethyl)-3,5-dimethylpyridine (4.5 g, 66.1%,) as a brown thicksyrup. ¹H NMR: 200 MHz, CDCl₃: δ 8.15 (s, 1H), 7.45 (s, 1H), 4.75 (s,2H), 2.35 (s, 3H), 2.25 (s, 3H). MS: [M+H]+: m/z=156.3.

4-(4-((3,5-dimethylpyridin-2-yl)methoxy)phenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one

4-(4-Hydroxyphenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (3.0g, 9.6 mmol) was added to a mixture of cesium carbonate (12.6 g, 38.6mmol) and DMF (1000 mL) at RT under an atmosphere of nitrogen. Thereaction mixture was stirred at RT for 30 min upon which2-(chloromethyl)-3,5-dimethylpyridine (2.25 g, 14.5 mmol) was added. Thereaction mixture was heated for 4 h at 80° C. (the reaction wasmonitored by TLC). The reaction mixture was diluted with water andextracted with EtOAc. The combined organics were dried over sodiumsulfate, filtered and concentrated under reduced pressure. The residuewas purified by flash column chromatography using 15% ethyl acetate inn-hexane and silica gel (230-400 mesh) to afford4-(4-((3,5-dimethylpyridin-2-yl)methoxy)phenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one(3.2 g, 65.3%,) as an off-white solid. ¹H NMR: 500 MHz, DMSO-d₆: δ 8.2(s, 1H), 7.65 (d, 2H), 7.45 (s, 1H), 7.15 (d, 2H), 7.1 (d, 2H), 7.0 (d,2H), 5.2 (s, 2H), 3.8 (s, 3H), 2.35 (s, 3H), 2.3 (s, 3H), 1.45 (s, 6H).MS: [M+H]+: m/z=430.4. HPLC (96.3%, Condition-A).

4-(4-((3,5-dimethylpyridin-2-yl)methoxy)phenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-onemethanesulfonate

Methanesulfonic acid (445.0 mg, 4.6 mmol) was added to a solution of4-(4-((3,5-dimethylpyridin-2-yl)methoxy)phenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one(2.01 g, 4.6 mmol) in DCM (3 ml) and diethyl ether (150 mL) at RT underan atmosphere of nitrogen. The reaction mixture was stirred at RT for 4h and the solids were removed by filtration. The solid was washed with20% DCM in diethyl ether and dried under vacuo to afford4-(4-((3,5-dimethylpyridin-2-yl)methoxy)phenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-onemethanesulfonate (2.1 g, 87%) as a white solid. ¹H NMR: 500 MHz,DMSO-d₆: δ 8.2 (s, 1H), 7.65 (d, 2H), 7.45 (s, 1H), 7.15 (d, 2H), 7.1(d, 2H), 7.0 (d, 2H), 5.2 (s, 2H), 3.8 (s, 3H), 2.35 (s, 3H), 2.3 (s,3H), 1.45 (s, 6H), HPLC: (98.9%, Condition-A).

2-(Chloromethyl)imidazo[1,2-a]pyridine

1,3-Dichloroacetone (22.9 g, 180.3 mmol) was added to a solution of2-amino pyridine (10 g, 106.3 mmol) in acetonitrile (200 ml). Themixture was heated at reflux for 14 h (the reaction was monitored byTLC). Upon completion of the reaction, the volatiles were removed underreduced pressure. The residue was diluted with water and adjusted the pHto 7.5 with sodium bicarbonate solution which was extracted with EtOAc.The combined organics were dried over sodium sulfate, filtered andconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography using 12% ethyl acetate in n-hexanes and silicagel (230-400 mesh) to afford 2-(chloromethyl) imidazo[1,2-a]pyridine(8.0 g, 47.9%,) as pale yellow solid. ¹H NMR: 200 MHz, CDCl₃: δ 8.15 (d,1H), 7.6 (dd, 2H), 7.1 (t, 1H), 6.8 (t, 1H), 4.75 (s, 2H). MS: [M+H]+:m/z=167.2.

4-(4-(Imidazo[1,2-a]pyridin-2-ylmethoxy)phenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one

4-(4-Hydroxyphenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (2.5g, 8.06 mmol) was added to a mixture of cesium carbonate (10.5 g, 32.2mmol) and DMF (20 mL) at RT under nitrogen. The reaction mixture wasstirred at RT for 30 min, upon which2-(chloromethyl)imidazo[1,2-a]pyridine (2.4 g, 12.0 mmol) was added. Themixture was heated at 80° C. for 4 h (reaction was monitored by TLC).The reaction mixture was allowed to cool to RT, diluted with water andextracted with EtOAc. The combined organics were dried over sodiumsulfate, filtered and concentrated under reduced pressure. The residuewas purified by flash column chromatography using 20% ethyl acetate inn-hexane and silica gel (230-400 mesh), to afford4-(4-(imidazo[1,2-a]pyridin-2-ylmethoxy)phenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one(2.8 g, 77.7%,) as Off-white solid. ¹H NMR: 500 MHz, DMSO-d₆: δ 8.55 (d,1H), 8.0 (s, 1H), 7.55 (Ar, 3H), 7.3-6.85 (Ar, 8H), 5.15 (s, 2H) 3.85(s, 3H), 1.25 (s, 6H). MS: [M+H]+: m/z=441.2. HPLC: (97.3%,Condition-A).

4-(4-(Imidazo[1,2-a]pyridin-2-ylmethoxy)phenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-onemethanesulfonate

Methanesulfonic acid (531 mg, 5.5 mmol) was added to a solution of4-(4-(imidazo[1,2-a]pyridin-2-ylmethoxy)phenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one(2.5 g, 5.5 mmol) in DCM (5 ml) and diethyl ether (150 mL) at RT underan atmosphere of nitrogen. The reaction mixture was stirred for afurther 4 h at RT. The solids were collected by filtration, washed with20% DCM in diethyl ether and dried in vacuo to afford4-(4-(imidazo[1,2-a]pyridin-2-ylmethoxy)phenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-onemethanesulfonate (2.4 g, 82.7%,) as white solid. ¹H NMR: 500 MHz,DMSO-d₆: δ 8.75 (d, 1H), 8.1 (s, 1H), 7.65 (Ar, 3H), 7.3-6.85 (Ar, 8H),5.2 (s, 2H) 3.85 (s, 3H), 1.25 (s, 6H), HPLC: (98.8%, Condition-A).

6-Chloroimidazo[1,2-b]pyridazine

Bromoacetaldehyde diethylacetal (36.5 g, 216 mmol) was added to asolution of aq.cHBr (7.2 ml) and then heated to reflux for 30 min. Themixture was then cooled to 0° C., upon which ethanol (236 ml), sodiumbicarbonate (8.09 g, 95 mmol) and 6-chloropyridazin-3-amine (4 g, 30mmol) were added. The mixture was heated to 80° C. for 3 h (reaction wasmonitored by TLC) and then allowed to cool to RT. The mixture wasconcentrated under reduced pressure, diluted with water and extractedwith EtOAc. The combined organics were dried over sodium sulfate,filtered and concentrated under reduced pressure. The residue waspurified by flash column chromatography using 15% ethyl acetate inn-hexane and silica gel (230-400 mesh), to afford6-chloroimidazo[1,2-b]pyridazine (4.0 g, 85.2%,) as Off-white solid. ¹HNMR: 200 MHz, CDCl₃: δ 7.4-7.2 (Ar, 4H), 3.85 (q, 1H), 3.4 (q, 1H), 3.2(q, 2H), 1.35 (t, 3H), 1.1 (t, 3H). MS: [M+H]+: m/z=154.3.

Methylimidazo[1,2-b]pyridazine-6-carboxylate

6-Chloroimidazo[1,2-b]pyridazine (5.0 g, 32 mmol) was added to asolution of methanol (75 ml) and acetonitrile (75 ml) in a steel bomb atRT under nitrogen bubbling. Triethylamine (4.0 g, 39.4 mmol), BINAP (2.0g, 3.0 mmol) and bisacetonitrile palladium dichloride (0.854 g, 3.0mmol) were then added to the mixture. The mixture was heated to 100° C.which was maintained for approximately 10 hours (the reaction wasmonitored by TLC). The reaction mixture was filtered through a bed ofCelite® washing with ethyl acetate. The organics were washed with waterand brine, dried over sodium sulfate and concentrated under reducedpressure. The residue was purified by flash column chromatography using10% ethyl acetate in n-hexane and silica gel (230-400 mesh) to affordmethyl imidazo[1,2-b]pyridazine-6-carboxylate (2.5 g, 43%,) as anoff-white solid. ¹H NMR: 200 MHz, DMSO-d₆₃: δ 8.55 (s, 1H), 8.3 (d, 1H),7.95 (s, 1H), 7.55 (d, 1H), 3.95 (s, 3H). MS: [M+H]+: m/z=177.9.

Imidazo[1,2-b]pyridazin-6-ylmethanol

Sodium borohydride (1.1 g, 31.1 mmol) was added to a solution of methylimidazo[1,2-b]pyridazine-6-carboxylate (2.4 g, 15.5 mmol) in THF (35 mL)and methanol (2.5 ml) at RT. The reaction mixture was stirred at RT for2 h (the reaction was monitored by TLC) upon which the mixture wasconcentrated under reduced pressure. The reaction mixture was dilutedwith water and extracted with EtOAc. The combined organics were driedover sodium sulfate, filtered and concentrated under reduced pressure toafford imidazo[1,2-b]pyridazin-6-ylmethanol (1.6 g, 81%,) as a whitesolid. ¹H NMR: 200 MHz, DMSO-d₆: δ 8.5 (s, 1H), 8.3 (d, 1H), 7.9 (s,1H), 7.55 (d, 1H), 5.65 (t, 1H), 4.6 (d, 2H). MS: [M+H]+: m/z=311.2.

6-(Chloromethyl)imidazo[1,2-b]pyridazine

Thionyl chloride (10 ml) was added toimidazo[1,2-b]pyridazin-6-ylmethanol (1.5 g, 9.0 mmol) at 20° C. underan atmosphere of nitrogen at RT. The reaction mixture was stirred atreflux for 3 h (the reaction was monitored by TLC) upon which thevolatiles were removed under reduced pressure. The reaction mixture wasdiluted with water and extracted with EtOAc. The combined organics weredried over sodium sulfate, filtered and concentrated under reducedpressure. The residue was purified by flash column chromatography using15% ethyl acetate in n-hexane and silica gel (230-400 mesh) to afford6-(chloromethyl)imidazo[1,2-b]pyridazine (1.2 g, 69%,) as an off-whitesolid. ¹H NMR, 200 MHz, DMSO-d₆: δ 8.35 (s, 1H), 8.3 (d, 1H), 7.85 (s,1H), 7.35 (d, 1H), 4.95 (s, 2H). MS: [M+H]+: m/z=149.9.

4-(4-(Imidazo[1,2-b]pyridazin-6-ylmethoxy)phenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one

4-(4-Hydroxyphenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (1.2g, 3.8 mmol) was added to a mixture of cesium carbonate (3.7 g, 11.6mmol) and DMF (25 mL) at RT under an atmosphere of nitrogen. Thereaction mixture was stirred at RT for 30 min upon which6-(chloromethyl)imidazo[1,2-b]pyridazine (0.96 g, 5 mmol) was added. Themixture was heated at 80° C. for 4 h (the reaction was monitored byTLC). The reaction mixture was diluted with water and extracted withEtOAc. The combined organics were dried over sodium sulfate, filteredand concentrated under reduced pressure. The residue was purified byflash column chromatography using 30% ethyl acetate in n-hexane andsilica gel (230-400 mesh) to afford4-(4-(imidazo[1,2-b]pyridazin-6-ylmethoxy)phenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one(0.8 g, 47%,) as Off-white solid. ¹H NMR: 200 MHz, DMSO-d₆: δ 8.35 (s,1H), 8.2 (d, 1H), 7.8 (s, 1H), 7.55 (d, 2H), 7.4 (d, 1H), 7.2 (d, 2H),7.1 (d, 2H), 7.0 (d, 2H), 5.3 (s, 2H) 3.9 (s, 3H), 1.45 (s, 6H). MS:[M+H]+: m/z=442.1. HPLC: (95.8%, Condition-A).

4-(4-(Imidazo[1,2-b]pyridazin-6-ylmethoxy)phenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-onemethanesulfonate

Methanesulfonic acid (54 mg, 0.5 mmol) was added to a solution ofcompound4-(4-(imidazo[1,2-b]pyridazin-6-ylmethoxy)phenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one(250 mg, 0.5 mmol) in DCM (2 ml) and diethyl ether (20 mL) at RT underan atmosphere of nitrogen. The reaction mixture was stirred at RT for 4h upon which the mixture was filtered and the solids were washed with20% DCM in diethyl ether and dried in vacuo to afford4-(4-(imidazo[1,2-b]pyridazin-6-ylmethoxy)phenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-onemethanesulfonate (240 mg, 80.0%,) as an off-white solid. ¹H NMR: 200MHz, DMSO-d₆: δ 8.55 (s, 1H), 8.35 (d, 1H), 78.1 (s, 1H), 7.65 (d, 2H),7.4 (d, 1H), 7.2 (d, 2H), 7.1 (d, 2H), 7.0 (d, 2H), 5.35 (s, 2H) 3.9 (s,3H), 2.35 (s, 3H), 1.45 (s, 6H). HPLC: (98.3%, Condition-A).

6-Chloro-2-(chloromethyl)imidazo[1,2-b]pyridazine

1,3-Dichloroacetone (21.4 g, 168.0 mmol) was added to a solution of6-chloropyridazin-3-amine (10 g, 77.2 mmol) in acetonitrile (200 ml).The mixture was heated at reflux for 14 h (the reaction was monitored byTLC). The volatiles were removed under reduced pressure and the reactionmixture was diluted with water. The pH was adjusted to ˜7.5 with sodiumbicarbonate solution and then extracted with EtOAc. The combinedorganics were dried over sodium sulfate, filtered and concentrated underreduced pressure. The residue was purified by flash columnchromatography using 14% ethyl acetate in n-hexane and silica gel(230-400 mesh) to afford6-chloro-2-(chloromethyl)imidazo[1,2-b]pyridazine (6.0 g, 64.1%,) aswhite solid. ¹H NMR: 200 MHz, CDCl₃: δ 8.0 (s, 1H), 7.9 (d, 1H), 7.1 (d,1H), 4.75 (s, 2H). MS: [M+H]+: m/z=202.8.

4-(4-((6-Chloroimidazo[1,2-b]pyridazin-2-yl)methoxy)phenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one

4-(4-Hydroxyphenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (200mg, 0.64 mmol) was added to a mixture of cesium carbonate (838 mg, 2.5mmol) and DMF (5 mL) at RT under an atmosphere of nitrogen. The reactionmixture was stirred at RT for 30 min upon which6-chloro-2-(chloromethyl)imidazo[1,2-b]pyridazine (196 mg, 9.6 mmol) wasadded. The mixture was heated at 80° C. for 4 h (the reaction wasmonitored by TLC). The reaction mixture was diluted with water andextracted with EtOAc; the combined organics were dried over sodiumsulfate, filtered and concentrated under reduced pressure. The organicresidue was purified by flash column chromatography using 30% ethylacetate in n-hexane and silica gel (230-400 mesh) to afford4-(4-((6-chloroimidazo[1,2-b]pyridazin-2-yl)methoxy)phenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one(180 mg, 63.0%,) as an off-white solid. ¹H NMR, 500 MHz, DMSO-d₆: δ 8.45(s, 1H), 8.2 (d, 1H), 7.55 (d, 2H), 7.4 (d, 1H), 7.15 (d, 2H), 7.1 (d,2H), 7.0 (d, 2H), 5.25 (s, 2H) 3.8 (s, 3H), 1.25 (s, 6H). MS: [M+H]+:m/z=476.7. HPLC: (96.7%, Condition-A).

4-(4-(Imidazo[1,2-b]pyridazin-2-ylmethoxy)phenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one

Palladium hydroxide (36 mg) was added to a solution of4-(4-((6-chloroimidazo[1,2-b]pyridazin-2-yl)methoxy)phenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one(180 mg, 0.37 mmol) and diethyl amine (28 mg, 0.37) in methanol (25 ml)at RT under an atmosphere of nitrogen. The nitrogen atmosphere wasexchanged for hydrogen and was stirred at RT for 2 h (the reaction wasmonitored by TLC). The compound was filtered through a bed of Celite®bed washing with methanol. The filtrate was concentrated under reducedpressure to afford4-(4-(imidazo[1,2-b]pyridazin-2-ylmethoxy)phenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one(160 mg, 96.7%,) as a white solid. ¹H NMR: 500 MHz, DMSO-d₆: δ 8.45 (s,1H), 8.4 (s, 1H) 8.15 (d, 1H), 7.55 (d, 2H), 7.25 (d, 1H), 7.15 (d, 2H),7.1 (d, 2H), 7.0 (d, 2H), 5.25 (s, 2H) 3.8 (s, 3H), 1.25 (s, 6H). MS:[M+H]+: m/z=442.3. HPLC: (97.4%, Condition-A).

4-(4-(Imidazo[1,2-b]pyridazin-2-ylmethoxy)phenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-onemethanesulfonate

Methanesulfonic acid (34.8 mg, 0.36 mmol) was added to a solution ofcompound4-(4-(imidazo[1,2-b]pyridazin-2-ylmethoxy)phenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one(160 mg, 0.36 mmol) in DCM (3 ml) and diethyl ether (15 mL) at RT underan atmosphere of nitrogen. The reaction mixture was stirred at RT for 4h, upon which the mixture was filtered and the solids were washed with20% DCM in diethyl ether. The solids were dried under vacuo to afford4-(4-(imidazo[1,2-b]pyridazin-2-ylmethoxy)phenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-onemethanesulfonate (110 mg, 56%,) as a white solid. ¹H NMR: 500 MHz,DMSO-d₆: δ 8.45 (s, 1H), 8.4 (s, 1H) 8.15 (d, 1H), 7.55 (d, 2H), 7.25(d, 1H), 7.15 (d, 2H), 7.1 (d, 2H), 7.0 (d, 2H), 5.25 (s, 2H) 3.8 (s,3H), 2.35 (s, 3H), 1.25 (s, 6H), HPLC: (98.5%, Condition-A).

4-(3-(4-((3,5-dimethylpyridin-2-yl)methoxy)phenyl)-5,5-dimethyl-4-oxo-4,5-dihydrofuran-2-yl)benzonitrile

4-(3-(4-Hydroxyphenyl)-5,5-dimethyl-4-oxo-4,5-dihydrofuran-2-yl)benzonitrile(1.5 g, 4.9 mmol) was added to a mixture of carbonate (6.3 g, 19.6 mmol)and DMF (100 mL) at RT under nitrogen. The reaction mixture was stirredat RT for 30 min upon which 2-(chloromethyl)-3,5-dimethylpyridine (1.14g, 7.3 mmol) was added. The mixture was heated at 80° C. for 4 h (thereaction was monitored by TLC). The reaction mixture was diluted withwater and extracted with EtOAc; the combined organics were dried oversodium sulfate, filtered and concentrated under reduced pressure. Theresidue was purified by flash column chromatography using 22% ethylacetate in n-hexane and silica gel (230-400 mesh) to afford4-(3-(4-((3,5-dimethylpyridin-2-yl)methoxy)phenyl)-5,5-dimethyl-4-oxo-4,5-dihydrofuran-2-yl)(0.70 g, 35%,) as yellow solid. ¹H NMR, 200 MHz, CDCl₃: δ 7.45-6.8 (Ar,11H), 4.9 (d, 1H), 4.6 (d, 1H), 3.75 (s, 3H), 3.2 (d, 2H) 3.1 (q, 1H),2.5 (q, 1H) 0.95 (t, 6H). MS: [M+H]+: m/z=425.2. HPLC: (96.3%,Condition-A).

4-(3-(4-((3,5-Dimethylpyridin-2-yl)methoxy)phenyl)-5,5-dimethyl-4-oxo-4,5-dihydrofuran-2-yl)benzonitrilemethanesulfonate

Methanesulfonic acid (158 mg, 1.6 mmol) was added to a solution ofcompound4-(3-(4-((3,5-dimethylpyridin-2-yl)methoxy)phenyl)-5,5-dimethyl-4-oxo-4,5-dihydrofuran-2-yl)(700 mg, 1.6 mmol) in DCM (0.5 ml) and diethyl ether (15 mL) at RT underan atmosphere of nitrogen. The reaction mixture was stirred at RT for 4h upon which, the mixture was filtered and the solids were washed with20% DCM in diethyl ether and dried in vacuo to afford4-(3-(4-((3,5-dimethylpyridin-2-yl)methoxy)phenyl)-5,5-dimethyl-4-oxo-4,5-dihydrofuran-2-yl)benzonitrilemethanesulfonate (2.1 g, 75%,) as a white solid. ¹H NMR: 200 MHz, CDCl₃:δ 8.2 (d, 1H), 7.5 (t, 1H), 7.3-6.8 (Ar, 9H) 5.1 (s, 2H), 4.05 (s, 2H),3.8 (s, 3H), HPLC: (97.1%, Condition-A).

4-(3-(4-(Imidazo[1,2-a]pyridin-2-ylmethoxy)phenyl)-5,5-dimethyl-4-oxo-4,5-dihydrofuran-2-yl)benzonitrile

4-(3-(4-Hydroxyphenyl)-5,5-dimethyl-4-oxo-4,5-dihydrofuran-2-yl)benzonitrile(3.15 g, 10.3 mmol) was added to a mixture of cesium carbonate (13.4 g,41.3 mmol) and DMF (100 mL) at RT under an atmosphere of nitrogen. Thereaction mixture was stirred at RT for 30 min upon which2-(chloromethyl)imidazo[1,2-a]pyridine (2.0 g, 12.3 mmol) was added. Themixture was heated at 80° C. for 4 h (the reaction was monitored byTLC). The reaction mixture was diluted with water and extracted withEtOAc, the combined organics were dried over sodium sulfate, filteredand concentrated under reduced pressure. The residue was purified byflash column chromatography using 20% ethyl acetate in n-hexane andsilica gel (230-400 mesh) to afford4-(3-(4-(imidazo[1,2-a]pyridin-2-ylmethoxy)phenyl)-5,5-dimethyl-4-oxo-4,5-dihydrofuran-2-yl)benzonitrile(2.7 g, 60%,) as an off-white solid. ¹H NMR: 500 MHz, DMSO-d₆: δ 8.55(d, 1H), 8.0 (s, 1H), 7.55 (Ar, 3H), 7.3-6.85 (Ar, 8H), 5.15 (s, 2H),1.25 (s, 6H). MS: [M+H]+: m/z=436.2. HPLC: (97.3%, Condition-A).

4-(3-(4-(Imidazo[1,2-a]pyridin-2-ylmethoxy)phenyl)-5,5-dimethyl-4-oxo-4,5-dihydrofuran-2-yl)benzonitrilemethanesulfonate

Methanesulfonic acid (309 mg, 3.2 mmol) was added to a solution ofcompound4-(3-(4-(imidazo[1,2-a]pyridin-2-ylmethoxy)phenyl)-5,5-dimethyl-4-oxo-4,5-dihydrofuran-2-yl)benzonitrile(1.4 g, 3.2 mmol) in DCM (5 ml) and diethyl ether (30 mL) at RT under anatmosphere of nitrogen. The reaction mixture was stirred at RT for 4 hupon which it was filtered and the solids were washed with 20% DCM indiethyl ether and dried in vacuo to afford4-(3-(4-(imidazo[1,2-a]pyridin-2-ylmethoxy)phenyl)-5,5-dimethyl-4-oxo-4,5-dihydrofuran-2-yl)benzonitrilemethanesulfonate (1.1 g, 64%,) as a white solid. ¹H NMR: 500 MHz,DMSO-d₆: δ 8.55 (d, 1H), 8.0 (s, 1H), 7.55 (Ar, 3H), 7.3-6.85 (Ar, 8H),5.15 (s, 2H) 2.15 (s, 3H), 1.25 (s, 6H), HPLC: (98.5%, Condition-A).

3-Chloro-2-(chloromethyl)imidazo[1,2-a]pyridine

N-Chloro succinimide (329 g, 2.46 mmol) was added to a solution of2-(chloromethyl)imidazo[1,2-a]pyridine (450 mg, 2.2 mmol) in DCM (15 ml)at RT under an atmosphere of nitrogen. Stirring was continued for 2 h(reaction was monitored by TLC) upon which the reaction mixture wasdiluted with DCM and washed with water and brine solution. The organiclayer was dried over sodium sulfate, filtered and concentrated underreduced pressure. The residue was purified by flash columnchromatography using 10% ethyl acetate in n-hexane and silica gel(230-400 mesh) to afford 3-chloro-2-(chloromethyl)imidazo[1,2-a]pyridine(400 mg, 76%,) as Off-white solid. ¹H NMR: 200 MHz, CDCl₃: δ 8.4 (d,1H), 7.7 (d, 1H), 7.5 (t, 1H), 7.1 (t, 1H), 4.85 (s, 2H). MS: [M+H]+:m/z=201.8. HPLC: (98.3%, Condition-A).

4-(4-((3-Chloroimidazo[1,2-a]pyridin-2-yl)methoxy)phenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one

4-(4-Hydroxyphenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (200mg, 0.64 mmol) was added to a mixture of cesium carbonate (843 mg, 2.5mmol) and DMF (20 mL) at RT under an atmosphere of nitrogen. Thereaction mixture was stirred at RT for 30 min, upon which3-chloro-2-(chloromethyl)imidazo[1,2-a]pyridine (183 mg, 0.77 mmol) wasadded. The mixture was heated at 80° C. for 4 h (the reaction wasmonitored by TLC) upon which, the mixture was diluted with water andextracted with EtOAc. The combined organics were dried over sodiumsulfate, filtered and concentrated under reduced pressure. The residuewas purified by flash column chromatography using 18% ethyl acetate inn-hexane and silica gel (230-400 mesh) to afford4-(4-((3-chloroimidazo[1,2-a]pyridin-2-yl)methoxy)phenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one(250 mg, 81%,) as an off-white solid. ¹H NMR: 500 MHz, DMSO-d₆: δ 8.4(d, 1H), 7.7 (d, 1H), 7.55 (Ar, 3H), 7.7-6.9 (Ar, 10H), 5.2 (s, 2H) 3.8(s, 3H), 1.4 (s, 6H). MS: [M+H]+: m/z=470.7. HPLC: (97.2%, Condition-A).

4-(4-((3-Chloroimidazo[1,2-a]pyridin-2-yl)methoxy)phenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-onemethanesulfonate

Methanesulfonic acid (50.5 mg, 0.52 mmol) was added to a solution of4-(4-((3-chloroimidazo[1,2-a]pyridin-2-yl)methoxy)phenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one(250 mg, 0.52 mmol) in DCM (2.5 ml) and diethyl ether (25 mL) at RTunder an atmosphere of nitrogen. The reaction mixture was stirred at RTfor 4 h upon which the compound was filtered, washed with 20% DCM indiethyl ether and dried in vacuo to afford4-(4-((3-chloroimidazo[1,2-a]pyridin-2-yl)methoxy)phenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-onemethanesulfonate (260 mg, 86%,) as white solid. ¹H NMR: 500 MHz,DMSO-d₆: δ 8.55 (d, 1H), 8.0 (s, 1H), 7.65 (Ar, 3H), 7.3-6.85 (Ar, 7H),5.2 (s, 2H) 3.85 (s, 3H), 2.15 (s, 3H) 1.25 (s, 6H), HPLC: (98.8%,Condition-A).

Methyl 5-methylpicolinate

2-Chloro-5-methylpyridine (10 g, 78 mmol) was added to a solution ofmethanol (75 ml) and acetonitrile (75 ml) in steel bomb at RT undernitrogen bubbling followed by the addition of triethylamine (11.8 g, 117mmol), BINAP (970 mg, 1.5 mmol) and bisacetonitrile palladium dichloride(0.4 g, 1.5 mmol). The mixture was heated to 100° C. and thistemperature was maintained over night (the reaction was monitored byTLC). The reaction mixture was filter through Celite® bed and washingwith ethyl acetate. The filtrate was washed with water and brine. Theorganic layer was concentrated under reduced pressure and purified byflash column chromatography using 10% ethyl acetate in n-hexane andsilica gel (230-400 mesh) to afford methyl 5-methylpicolinate (6.5 g,55%,) as an off-white solid. ¹H NMR: 200 MHz, CDCl₃: δ 8.6 (s, 1H), 8.0(d, 1H), 7.65 (d, 1H), 4.05 (s, 3H), 2.4 (s, 3H). MS: [M+H]+: m/z=151.9.

(5-Methylpyridin-2-yl)methanol

Sodium borohydride (4.5 g, 115. mmol) was added to a solution of methyl5-methylpicolinate (6.0 g, 39.5 mmol) in THF (60 mL) and methanol (6 ml)at RT. The reaction mixture was stirred at RT for 2 h (the reaction wasmonitored by TLC). The mixture was concentrated under reduced pressureand the residue was diluted with water and extracted with EtOAc. Thecombined organics were dried over sodium sulfate, filtered andconcentrated under reduced pressure. The organic layer was concentratedunder vacuo to afford (5-methylpyridin-2-yl)methanol (3.5 g, 72.9%,) asan off-white solid. ¹H NMR: 200 MHz, CDCl₃: δ 8.5 (s, 1H), 7.7 (d, 1H),7.15 (d, 1H), 5.0 (s, 3H), 3.4 (s, 3H). MS: [M+H]+: m/z=124.0.

2-(Chloromethyl)-5-methylpyridine

Thionyl chloride (30 ml) was added to (5-methylpyridin-2-yl)methanol(3.0 g, 24.3 mmol) at 20° C. under nitrogen. The reaction mixture wasstirred at reflux for 3 h (the reaction was monitored by TLC). Thereaction mixture was concentrated under reduced pressure upon which itwas diluted with water and extracted with EtOAc. The combined organicswere dried over sodium sulfate, filtered and concentrated under reducedpressure. The residue was purified by flash column chromatography using6% ethyl acetate in n-hexane and silica gel (230-400 mesh), to afford2-(chloromethyl)-5-methylpyridine (2.5 g, 73%,) as an off-white solid.¹H NMR: 200 MHz, CDCl₃: δ 8.4 (s, 1H), 7.5 (d, 1H), 7.3 (d, 1H), 4.6 (s,2H), 2.3 (s, 3H). MS: [M+H]+: m/z=142.2.

5-(4-Methoxyphenyl)-2,2-dimethyl-4-(4-((5-methylpyridin-2-yl)methoxy)phenyl)furan-3(2H)-one

4-(4-Hydroxyphenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one(2.0, 6.5 mmol) was added to a mixture of cesium carbonate (10.5 g, 32.2mmol) and DMF (50 mL) at RT under an atmosphere of nitrogen. Thereaction mixture was stirred at RT for 30 min, upon which2-(chloromethyl)-5-methylpyridine (1.36 g, 9.6 mmol) was added. Themixture was heated at 80° C. for 4 h (the reaction was monitored byTLC). The reaction mixture allowed to cool, diluted with water andextracted with EtOAc. The combined organics were dried over sodiumsulfate, filtered and concentrated under reduced pressure. The residuewas purified by flash column chromatography using 20% ethyl acetate inn-hexane and silica gel (230-400 mesh), to afford5-(4-methoxyphenyl)-2,2-dimethyl-4-(4-((5-methylpyridin-2-yl)methoxy)phenyl)furan-3(2H)-one(2.0 g, 76.9%,) as an off-white solid. ¹H NMR: 200 MHz, DMSO-d₆: δ 8.4(s, 1H), 7.6 (d, 1H), 7.55 (d, 2H), 7.4 (d, 1H), 7.2 (d, 2H), 7.1 (d,2H), 7.0 (d, 2H), 5.2 (s, 2H) 3.8 (s, 3H), 2.3 (s, 3H), 1.45 (s, 6H).MS: [M+H]+: m/z=415.2. HPLC: (97.5%, Condition-A).

5-(4-Methoxyphenyl)-2,2-dimethyl-4-(4-((5-methylpyridin-2-yl)methoxy)phenyl)furan-3(2H)-onemethanesulfonate

Methanesulfonic acid (462 mg, 4.8 mmol) was added to a solution of5-(4-methoxyphenyl)-2,2-dimethyl-4-(4-((5-methylpyridin-2-yl)methoxy)phenyl)furan-3(2H)-one(2.0 g, 4.8 mmol) in DCM (5 ml) and diethyl ether (50 mL) at RT under anatmosphere of nitrogen. The reaction mixture was stirred at RT for 4 hupon which the solids were collected by filtration, washed with 20% DCMin diethyl ether and dried in vacuo to afford5-(4-Methoxyphenyl)-2,2-dimethyl-4-(4-((5-methylpyridin-2-yl)methoxy)phenyl)furan-3(2H)-onemethanesulfonate (2.0 g, 90.9%,) as a white solid. ¹H NMR: 200 MHz,DMSO-d₆: δ 8.5 (s, 1H), 7.6 (d, 1H), 7.55 (d, 2H), 7.4 (d, 1H), 7.2 (d,2H), 7.1 (d, 2H), 7.0 (d, 2H), 5.2 (s, 2H) 3.8 (s, 3H), 2.35 (s, 3H),2.3 (s, 3H), 1.45 (s, 6H), HPLC: (99.3%, Condition-A).

4-(5,5-Dimethyl-3-(4-((5-methylpyridin-2-yl)methoxy)phenyl)-4-oxo-4,5-dihydrofuran-2-yl)benzonitrile

4-(3-(4-Hydroxyphenyl)-5,5-dimethyl-4-oxo-4,5-dihydrofuran-2-yl)benzonitrile(0.4 g, 1.3 mmol) was added to a mixture of cesium carbonate (1.7 g, 5.2mmol) and DMF (20 mL) at RT under nitrogen. The reaction mixture wasstirred at RT for 30 minutes upon which afford2-(chloromethyl)-5-methylpyridine (306 mg, 1.9 mmol) was added. Themixture was heated at 80° C. for 4 h (the reaction was monitored byTLC). The reaction mixture was diluted with water and extracted withEtOAc. The combined organics were dried over sodium sulfate, filteredand concentrated under reduced pressure. The residue was purified byflash column chromatography using 25% ethyl acetate in n-hexane andsilica gel (230-400 mesh) to afford4-(5,5-dimethyl-3-(4-((5-methylpyridin-2-yl)methoxy)phenyl)-4-oxo-4,5-dihydrofuran-2-yl)benzonitrile(160 mg, 30.1%,) as an off-white solid. ¹H NMR: 200 MHz, DMSO-d₆: δ 8.4(s, 1H), 7.6 (d, 1H), 7.55 (d, 2H), 7.4 (d, 1H), 7.2 (d, 2H), 7.1 (d,2H), 7.0 (d, 2H), 5.2 (s, 2H), 2.3 (s, 3H), 1.45 (s, 6H). MS: [M+H]+:m/z=411.2. HPLC: (97.3%, Condition-A).

4-(5,5-Dimethyl-3-(4-((5-methylpyridin-2-yl)methoxy)phenyl)-4-oxo-4,5-dihydrofuran-2-yl)benzonitrilemethanesulfonate

Methanesulfonic acid (36 mg, 0.3 mmol) was added to a solution of4-(5,5-dimethyl-3-(4-((5-methylpyridin-2-yl)methoxy)phenyl)-4-oxo-4,5-dihydrofuran-2-yl)benzonitrile(150 mg, 0.3 mmol) in DCM (5 ml) and diethyl ether (50 mL) at RT underan atmosphere of nitrogen. The reaction mixture was stirred at RT for 4h upon which the solids were collected by filtration, washed with 20%DCM in diethyl ether, dried in vacuo to afford4-(5,5-dimethyl-3-(4-((5-methylpyridin-2-yl)methoxy)phenyl)-4-oxo-4,5-dihydrofuran-2-yl)benzonitrilemethanesulfonate (120 mg, 67.0%,) as a white solid. ¹H NMR: 200 MHz,DMSO-d₆: δ 8.5 (s, 1H), 7.6 (d, 1H), 7.55 (d, 2H), 7.4 (d, 1H), 7.2 (d,2H), 7.1 (d, 2H), 7.0 (d, 2H), 5.2 (s, 2H), 2.35 (s, 3H), 2.3 (s, 3H),1.45 (s, 6H). HPLC: (98.3%, Condition-A).

Methyl 2-oxobutanoate

Trimethylsilyl chloride (1.06 g, 9.8 mmol) was added to a stirredsolution of 2-oxobutanoic acid (10.0 g, 98.0 mmol) in2,2-dimethoxypropane (90 ml) and methanol (20 ml). The mixture wasstirred for 18 hours at RT (the reaction was monitored by TLC) uponwhich the mixture was concentrated under reduced pressure afford crudemethyl 2-oxobutanoate (8.0 g) as a brown liquid. ¹H NMR: 200 MHz, CDCl₃:δ 3.85 (s, 3H), 2.9 (q, 2H), 1.15 (t, 1H), 6.8 (t, 1H), 4.75 (s, 2H).

Methyl 3-bromo-2-oxobutanoate

Copper bromide (30.0 g, 137 mmol) was added to a stirred solution ofmethyl 2-oxobutanoate (8.0 g, 68.9 mmol) in ethyl acetate (150 ml) andchloroform (100 ml). The mixture was stirred for 18 hours at reflux (thereaction was monitored by TLC). The mixture was filtered and washed withethyl acetate and the filtrates were concentrated in vacuo to affordcrude methyl 3-bromo-2-oxobutanoate (6.5 g) as a colorless liquid. ¹HNMR: 200 MHz, CDCl₃: δ 5.2 (q, 1H), 3.9 (s, 3H), 1.8 (d, 3H).

Methyl 3-methylimidazo[1,2-a]pyridine-2-carboxylate

Methyl 3-bromo-2-oxobutanoate (6.5 g, 34.3 mmol) was added to a stirredsolution of 2-aminopyridine (4.0 g, 42.5 mmol) in acetonitrile (100 ml).The mixture was heated at reflux for 14 h (the reaction was monitored byTLC). The mixture was concentrated in vacuo and the residue was dilutedwith water and the pH was to 7.5 using sodium bicarbonate solution. Themixture was extracted with EtOAc; the combined organics were dried oversodium sulfate, filtered and concentrated under reduced pressure. Theresidue was purified by flash column chromatography using 8% ethylacetate in n-hexane and silica gel (230-400 mesh) to afford methyl3-methylimidazo[1,2-a]pyridine-2-carboxylate (2.0 g, 25.1%,) as a paleyellow solid. ¹H NMR: 200 MHz, CDCl₃: δ 7.95 (d, 1H), 7.7 (d, 1H), 7.25(t, 1H), 6.8 (t, 1H), 4.0 (s, 3H), 2.8 (s, 3H). MS: [M+H]+: m/z=191.1.

(3-Methylimidazo[1,2-a]pyridin-2-yl)methanol

Sodium borohydride (1.5 g, 41.6 mmol) was added to a solution of methyl3-methylimidazo[1,2-a]pyridine-2-carboxylate (2.0 g, 10.5 mmol) in THF(50 mL) and methanol (2.5 ml) at RT. The reaction mixture was stirred atRT for 2 h (the reaction was monitored by TLC) upon which the mixturewas concentrated under reduced pressure. The residue was diluted withwater and extracted with EtOAc. The combined organics were dried oversodium sulfate, filtered and concentrated under reduced pressure toafford (3-methylimidazo[1,2-a]pyridin-2-yl)methanol (0.8 g, 47.05%,) asoff-white solid. ¹H NMR: 200 MHz, CDCl₃: δ 7.45 (d, 1H), 7.6 (d, 1H),7.2 (t, 1H), 6.8 (t, 1H), 4.85 (s, 2H), 2.45 (s, 3H). MS: [M+H]+:m/z=162.9.

2-(Chloromethyl)-3-methylimidazo[1,2-a]pyridine

Thionyl chloride (10 ml) was added to(3-methylimidazo[1,2-a]pyridin-2-yl)methanol (0.8 g, 4.9 mmol) at 20° C.under an atmosphere of nitrogen. The reaction mixture was stirred atreflux for 3 h (the reaction was monitored by TLC). The mixture wasconcentrated under reduced pressure, the residue was diluted with waterand extracted with EtOAc. The combined organics were dried over sodiumsulfate, filtered and concentrated under reduced pressure. The residuewas purified by flash column chromatography using 6% ethyl acetate inn-hexane and silica gel (230-400 mesh) to afford2-(chloroethyl)-3-methylimidazo[1,2-a]pyridine (400 mg, 45.4%,) as anoff-white solid. ¹H NMR: 200 MHz, CDCl₃: δ 8.15 (s, 1H), 7.6 (s, 1H),7.55 (d, 1H), 7.15 (d, 1H), 4.75 (s, 2H). MS: [M+H]+: m/z=181.3.

5-(4-Methoxyphenyl)-2,2-dimethyl-4-(4-((3-methylimidazo[1,2-a]pyridin-2-yl)methoxy)phenyl)furan-3(2H)-one

4-(4-Hydroxyphenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (0.1g, 0.32 mmol) was added to a mixture of cesium carbonate (0.52 g, 1.62mmol) and DMF (20 mL) at RT under an atmosphere of nitrogen. Thereaction mixture was stirred at RT for 30 min upon which2-(chloromethyl)-3-methylimidazo[1,2-a]pyridine (87 mg, 0.48 mmol) wasadded. The mixture was heated at for 4 h (the reaction was monitored byTLC). The reaction mixture was diluted with water and extracted withEtOAc, the combined organics were dried over sodium sulfate, filteredand concentrated under reduced pressure. The residue was purified byflash column chromatography using 20% ethyl acetate in n-hexane andsilica gel (230-400 mesh) to afford5-(4-methoxyphenyl)-2,2-dimethyl-4-(4-((3-methylimidazo[1,2-a]pyridin-2-yl)methoxy)phenyl)furan-3(2H)-one(2.8 g, 77%,) as an off-white solid. ¹H NMR, 500 MHz, DMSO-d₆: δ 8.25(d, 1H), 7.45 (d, 3H), 7.25 (t, 1H), 7.15-6.95 (Ar, 7H), 5.2 (s, 2H),3.85 (s, 3H), 2.45 (s, 3H), 1.45 (s, 6H). MS: [M+H]+: m/z=455.3. HPLC:(96.3%, Condition-A).

2-(Chloromethyl)-5-methylimidazo[1,2-a]pyridine

1,3-Dichloroacetone (17.6 g, 138.3 mmol) was added to a solution of6-methylpyridin-2-amine (10 g, 92.5 mmol) in acetonitrile (200 ml). Themixture was heated at reflux for 14 h (the reaction was monitored byTLC). The mixture was concentrated under reduced pressure, the residuewas diluted with water, and the pH was adjusted to 7.5 with sodiumbicarbonate solution. The mixture was extracted with EtOAc, the combinedorganics were dried over sodium sulfate, filtered and concentrated underreduced pressure. The residue was purified by flash columnchromatography using 10% ethyl acetate in n-hexane and silica gel(230-400 mesh) to afford 2-(chloromethyl)-5-methylimidazo[1,2-a]pyridine(7.0 g, 70.7%,) as a pale yellow solid. ¹H NMR: 200 MHz, CDCl₃: δ 8.15(s, 1H), 7.6 (dd, 2H), 7.1 (t, 1H), 6.8 (t, 1H), 4.95 (s, 2H), 2.6 (s,3H). MS: [M+H]+: m/z=181.5.

5-(4-Methoxyphenyl)-2,2-dimethyl-4-(4-((5-methylimidazo[1,2-a]pyridin-2-yl)methoxy)phenyl)furan-3(2H)-one

4-(4-Hydroxyphenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (250mg, 0.8 mmol) was added to a mixture of cesium carbonate (1.05 g, 3.22mmol) and DMF (20 mL) at RT under nitrogen. The reaction mixture wasstirred at RT for 30 minutes upon which2-(chloromethyl)-5-methylimidazo[1,2-a]pyridine (218 mg, 1.2 mmol) wasadded. The mixture was heated at for 4 h (the reaction was monitored byTLC) upon which the reaction mixture was diluted with water andextracted with EtOAc. The combined organics were dried over sodiumsulfate, filtered and concentrated under reduced pressure. The residuewas purified by flash column chromatography using 15% ethyl acetate inn-hexane and silica gel (230-400 mesh) to afford5-(4-methoxyphenyl)-2,2-dimethyl-4-(4-((5-methylimidazo[1,2-a]pyridin-2-yl)methoxy)phenyl)furan-3(2H)-one(280 mg, 77.7%,) as a light yellow solid. ¹H NMR: 500 MHz, DMSO-d₆: δ7.95 (s, 1H), 7.6 (d, 2H), 7.4 (d, 1H), 7.25 (t, 1H), 7.2 (d, 3H), 7.15(d, 2H), 7.0 (d, 2H), 6.8 (d, 1H), 5.2 (s, 2H) 3.85 (s, 3H), 2.6 (s,3H), 1.25 (s, 6H). MS: [M+H]+: m/z=455.6. HPLC: (97.3%, Condition-A).

5-(4-Methoxyphenyl)-2,2-dimethyl-4-(4-((5-methylimidazo[1,2-a]pyridin-2-yl)methoxy)phenyl)furan-3(2H)-onemethanesulfonate

Methanesulfonic acid (53.1 mg, 0.5 mmol) was added to a solution of5-(4-methoxyphenyl)-2,2-dimethyl-4-(4-((5-methylimidazo[1,2-a]pyridin-2-yl)methoxy)phenyl)furan-3(2H)-one(250 g, 0.5 mmol) in DCM (2.5 ml) and diethyl ether (50 mL) at RT underan atmosphere of nitrogen. The reaction mixture was stirred at RT for 4h upon which, the solids were collected by filtration, washed with 20%DCM in diethyl ether, dried in vacuo to afford5-(4-methoxyphenyl)-2,2-dimethyl-4-(4-((5-methylimidazo[1,2-a]pyridin-2-yl)methoxy)phenyl)furan-3(2H)-onemethanesulfonate (240 mg, 82.7%,) as white solid. ¹H NMR: 500 MHz,DMSO-d₆: δ 7.95 (s, 1H), 7.6 (d, 2H), 7.4 (d, 1H), 7.25 (t, 1H), 7.2 (d,3H), 7.15 (d, 2H), 7.0 (d, 2H), 6.8 (d, 1H), 5.2 (s, 2H) 3.85 (s, 3H),2.6 (s, 3H), 2.5 (s, 3H), 1.25 (s, 6H), HPLC: (98.4%, Condition-A).

6-Chloro-2-(chloromethyl)imidazo[1,2-a]pyridine

1,3-Dichloroacetone (7.4 g, 58.3 mmol) was added to a solution of5-chloropyridin-2-amine (5.0 g, 38.9 mmol) in acetonitrile (100 ml). Themixture was heated at reflux for 14 h (the reaction was monitored byTLC). Upon completion of the reaction as judged by TLC, the mixture wasconcentrated under reduced pressure. The residue was diluted with waterand the pH was adjusted to 7.5 with sodium bicarbonate solution. Themixture was extracted with EtOAc, the combined organics were dried oversodium sulfate, filtered and concentrated under reduced pressure. Theresidue was purified by flash column chromatography using 10% ethylacetate in n-hexane and silica gel (230-400 mesh) to afford6-chloro-2-(chloromethyl)imidazo[1,2-a]pyridine (1.5 g, 30%,) as a paleyellow solid. ¹H NMR: 200 MHz, CDCl₃: δ 8.0 (d, 1H), 7.6 (dd, 2H), 6.8(d, 1H), 4.75 (s, 2H). MS: [M+H]+: m/z=201.9.

4-(4-((6-Chloroimidazo[1,2-a]pyridin-2-yl)methoxy)phenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one

4-(4-Hydroxyphenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (300mg, 0.96 mmol) was added to a mixture of cesium carbonate (1.05 g, 3.8mmol) and DMF (20 mL) at RT under nitrogen. The reaction mixture wasstirred at RT for 30 minutes, upon which6-chloro-2-(chloromethyl)imidazo[1,2-a]pyridine (201 mg, 1.4 mmol) wasadded. The mixture was heated at 80° C. for 4 h (the reaction wasmonitored by TLC). Upon completion of the reaction as judged by TLC, thereaction mixture was diluted with water and extracted with EtOAc. Thecombined organics were dried over sodium sulfate, filtered andconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography using 20% ethyl acetate in n-hexane and silica gel(230-400 mesh) to afford4-(4-((6-chloroimidazo[1,2-a]pyridin-2-yl)methoxy)phenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (180 mg, 39.3%,) as a white solid.¹H NMR, 500 MHz, DMSO-d₆: δ 8.85 (s, 1H), 8.0 (s, 1H), 7.6 (d, 3H), 7.3(d, 1H), 7.15 (d, 2H), 7.1 (d, 2H), 7.0 (d, 2H), 5.15 (s, 2H) 3.8 (s,3H), 1.4 (s, 6H). MS: [M+H]+: m/z=475. HPLC: (98.0%, Condition-A).

4-(4-((6-Chloroimidazo[1,2-a]pyridin-2-yl)methoxy)phenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-onemethanesulfonate

Methanesulfonic acid (53.1 mg, 0.5 mmol) was added to a solution ofcompound4-(4-((6-chloroimidazo[1,2-a]pyridin-2-yl)methoxy)phenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one(250 g, 0.5 mmol) in DCM (2.5 ml) and diethyl ether (50 mL) at RT underan atmosphere of nitrogen. The reaction mixture was stirred at RT for 4h upon which the solids were collected by filtration, washed with 20%DCM in diethyl ether and dried in vacuo to afford4-(4-((6-chloroimidazo[1,2-a]pyridin-2-yl)methoxy)phenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-onemethanesulfonate (240 mg, 82%,) as a white solid. ¹H NMR: 500 MHz,DMSO-d₆: δ 8.8 (s, 1H), 8.3 (s, 1H), 8.0 (s, 1H), 7.6 (d, 2H), 7.4 (d,1H), 7.15 (d, 2H), 7.1 (d, 2H), 7.0 (d, 2H) 5.35 (s, 2H), 3.8 (s, 3H),2.3 (s, 3H), 1.4 (s, 6H), HPLC: (99.3%, Condition-A).

Tables

In the following tables, if a specific example contains multipleinstances of R₂, they will be separated by commas in the table (e.g. Me,Me or Et, Me). If the R₂ column contains a value “—group—” e.g.“—cyclopropyl—”, then both R₂ values are taken together to be a spiroring.

In a further aspect the compounds of the disclosure are embodied in withdistinct examples listed in the table below taken from Formula (I):

Example # HET X Z R₂ 1 A29

Me, Me 2 A29

Me, Me 3 A29

Me, Me 4 A29

Me, Me 5 A29

Me, Me 6 A29

Me, Me 7 A29

Me, Me 8 A29

Me, Me 9 A29

Me, Me 10 A29

Me, Me 11 A29

Me, Me 12 A29

Me, Me 13 A29

Me, Me 14 A29

Me, Me 15 A29

Me, Me 16 A29

Me, Me 17 A29

Me, Me 18 A29

Me, Me 19 A29

Me, Me 20 A29

Me, Me 21 A29

Me, Me 22 A29

Me, Me 23 A29

Me, Me 24 A29

Me, Me 25 A29

Me, Me 26 A29

Me, Me 27 A29

Me, Me 28 A29

Me, Me 29 A29

Me, Me 30 A29

Me, Me 31 A29

Me, Me 32 A29

Me, Me 33 A29

Me, Me 34 A29

Me, Me 35 A29

Me, Me 36 A29

Me, Me 37 A29

Me, Me 38 A29

Me, Me 39 A29

Me, Me 40 A29

Me, Me 41 A29

Me, Me 42 A29

Me, Me 43 A29

Me, Me 44 A29

Me, Me 45 A29

Me, Me 46 A29

Me, Me 47 A29

Me, Me 48 A29

Me, Me 49 A29

Me, Me 50 A29

Me, Me 51 A29

Me, Me 52 A29

Me, Me 53 A29

Me, Me 54 A29

Me, Me 55 A29

Me, Me 56 A29

Me, Me 57 A29

Me, Me 58 A29

Me, Me 59 A29

Me, Me 60 A29

Me, Me 61 A29

Me, Me 62 A29

Me, Me 63 A29

Me, Me 64 A29

Me, Me 65 A29

Me, Me 66 A29

Me, Me 67 A29

Me, Me 68 A29

Me, Me 69 A29

Me, Me 70 A29

Me, Me 71 A29

Me, Me 72 A29

Me, Me 73 A29

Me, Me 74 A29

Me, Me 75 A29

Me, Me 76 A29

Me, Me 77 A29

Me, Me 78 A29

Me, Me 79 A29

Me, Me 80 A29

Me, Me 81 A29

Me, Me 82 A29

Me, Me 83 A29

Me, Me 84 A29

Me, Me 85 A29

Me, Me 86 A29

Me, Me 87 A29

Me, Me 88 A29

Me, Me 89 A29

Me, Me 90 A29

Me, Me 91 A29

Me, Me 92 A29

Me, Me 93 A29

Me, Me 94 A29

Me, Me 95 A29

Me, Me 96 A29

Me, Me 97 A29

Me, Me 98 A29

Me, Me 99 A29

Me, Me 100 A29

Me, Me 101 A29

Me, Me 102 A29

Me, Me 103 A29

Me, Me 104 A29

Me, Me 105 A29

Me, Me 106 A29

Me, Me 107 A29

Me, Me 108 A29

Me, Me 109 A29

Me, Me 110 A29

Me, Me 111 A29

Me, Me 121 A29

Me, Me 122 A29

Me, Me 123 A29

Me, Me 124 A29

Me, Me 125 A29

Me, Me 126 A29

Me, Me 127 A29

Me, Me 128 A29

Me, Me 129 A29

Me, Me 130 A29

Me, Me 131 A29

Me, Me 132 A29

Me, Me 133 A29

Me, Me 134 A29

Me, Me 135 A29/

Me, Me 136 A29

Me, Me 137 A29

Me, Me 138 A29

Me, Me 139 A29

Me, Me 140 A29

Me Me 141 A29

Me, Me 142 A29

Me, Me 143 A29

Me, Me 144 A29

Me, Me 145 A29

Me, Me 146 A29

Me, Me 147 A29

Me, Me 148 A29

Me, Me 149 A29

Me, Me 150 A29

Me, Me 151 A29

Me, Me 152 A29

Me, Me 153 A29

Me, Me 154 A29

Me, Me 155 A29

Me, Me 156 A29

Me, Me 157 A29

Me, Me 158 A29

Me, Me 159 A29

Me, Me 160 A29

Me, Me 161 A29

Me, Me 162 A29

Me, Me 163 A29

Me, Me 164 A29

Me, Me 165 A29

Me, Me 166 A29

Me, Me 167 A29

Me, Me 168 A29

Me, Me 169 A29

Me, Me 170 A29

Me, Me 171 A29

Me, Me 172 A29

Me, Me 173 A29

Me, Me 174 A29

Me, Me 175 A29

Me, Me 176 A29

Me, Me 177 A29

Me, Me 178 A29

Me, Me 179 A29

Me, Me 180 A29

Me, Me 181 A29

Me, Me 182 A29

Me, Me 183 A29

Me, Me 184 A29

Me, Me 185 A29

Me, Me 186 A29

Me, Me 187 A29

Me, Me 188 A29

Me, Me 189 A29

Me, Me 190 A29

Me, Me 191 A29

Me, Me 192 A29

Me, Me 193 A29

Me, Me 194 A29

Me, Me 195 A29

Me, Me 196 A29

Me, Me 197 A29

Me, Me 198 A29

Me, Me 199 A29

Me, Me 200 A29

Me, Me 201 A29

Me, Me 202 A29

Me, Me 203 A29

Me, Me 204 A29

Me, Me 205 A29

Me, Me 206 A29

Me, Me 207 A29

Me, Me 211 A29

Me, Me 212 A29

Me, Me 213 A29

Me, Me 214 A29

Me, Me 215 A29

Me, Me 216 A29

Me, Me 217 A29

Me, Me 218 A29

Me, Me 219 A29

Me, Me 220 A29

Me, Me 221 A29

Me, Me 222 A29

Me, Me 223 A29

Me, Me 224 A29

Me, Me 225 A29

Me, Me 226 A29

Me, Me 227 A29

Me, Me 228 A29

Me, Me 229 A29

Me, Me 230 A29

Me, Me 231 A29

Me, Me 232 A29

Me, Me 233 A29

Me, Me 234 A29

Me, Me 235 A29

Me, Me 236 A29

Me, Me 237 A29

Me, Me 238 A29

Me, Me 239 A29

Me, Me 240 A29

Me, Me 241 A29

Me, Me 242 A29

Me, Me 243 A29

Me, Me 244 A29

Me, Me 245 A29

Me, Me 246 A29

Me, Me 247 A29

Me, Me 248 A29

Me, Me 249 A29

Me, Me 250 A29

Me, Me 251 A29

Me, Me 252 A29

Me, Me 253 A31

Me, Me 254 A31

Me, Me 255 A31

Me, Me 256 A31

Me, Me 257 A31

Me, Me 258 A31

Me, Me 259 A31

Me, Me 260 A31

Me, Me 261 A31

Me, Me 262 A31

Me, Me 263 A31

Me, Me 264 A31

Me, Me 265 A31

Me, Me 266 A31

Me, Me 267 A31

Me, Me 268 A31

Me, Me 269 A31

Me, Me 270 A31

Me, Me 271 A31

Me, Me 272 A31

Me, Me 273 A31

Me, Me 274 A31

Me, Me 275 A31

Me, Me 276 A31

Me, Me 277 A31

Me, Me 278 A31

Me, Me 279 A31

Me, Me 280 A31

Me, Me 281 A31

Me, Me 282 A31

Me, Me 283 A31

Me, Me 284 A31

Me, Me 285 A31

Me, Me 286 A31

Me, Me 287 A31

Me, Me 288 A31

Me, Me 289 A31

Me, Me 290 A31

Me, Me 291 A31

Me, Me 292 A31

Me, Me 293 A31

Me, Me 294 A31

Me, Me 295 A31

Me, Me 296 A31

Me, Me 297 A31

Me, Me 298 A31

Me, Me 299 A31

Me, Me 300 A31

Me, Me 301 A31

Me, Me 302 A31

Me, Me 303 A31

Me, Me 304 A31

Me, Me 305 A31

Me, Me 306 A31

Me, Me 307 A31

Me, Me 308 A31

Me, Me 309 A31

Me, Me 310 A31

Me, Me 311 A31

Me, Me 312 A31

Me, Me 313 A31

Me, Me 314 A31

Me, Me 315 A31

Me, Me 316 A31

Me, Me 317 A31

Me, Me 318 A31

Me, Me 319 A31

Me, Me 320 A31

Me, Me 321 A31

Me, Me 322 A31

Me, Me 323 A31

Me, Me 324 A31

Me, Me 325 A31

Me, Me 326 A31

Me, Me 327 A31

Me, Me 328 A31

Me, Me 329 A31

Me, Me 330 A31

Me, Me 331 A31

Me, Me 332 A31

Me, Me 333 A31

Me, Me 334 A31

Me, Me 335 A31

Me, Me 336 A31

Me, Me 337 A31

Me, Me 338 A31

Me, Me 339 A31

Me, Me 340 A31

Me, Me 341 A31

Me, Me 342 A31

Me, Me 343 A31

Me, Me 344 A31

Me, Me 345 A31

Me, Me 346 A31

Me, Me 347 A31

Me, Me 348 A31

Me, Me 349 A31

Me, Me 350 A31

Me, Me 351 A31

Me, Me 352 A31

Me, Me 353 A31

Me, Me 354 A31

Me, Me 355 A31

Me, Me 356 A31

Me, Me 357 A31

Me, Me 358 A31

Me, Me 359 A31

Me, Me 360 A31

Me, Me 361 A31

Me, Me 362 A31

Me, Me 363 A31

Me, Me 364 A31

Me, Me 365 A31

Me, Me 366 A31

Me, Me 367 A31

Me, Me 368 A31

Me, Me 369 A31

Me, Me 370 A31

Me, Me 371 A31

Me, Me 372 A31

Me, Me 373 A31

Me, Me 374 A31

Me, Me 375 A31

Me, Me 376 A31

Me, Me 377 A31

Me, Me 378 A31

Me, Me 379 A31

Me, Me 380 A31

Me, Me 381 A31

Me, Me 382 A31

Me, Me 383 A31

Me, Me 384 A31

Me, Me 385 A31

Me, Me 386 A31

Me, Me 387 A31

Me, Me 388 A31

Me, Me 389 A31

Me, Me 390 A31

Me, Me 391 A31

Me, Me 392 A31

Me, Me 393 A31

Me, Me 394 A31

Me, Me 395 A31

Me, Me 396 A31

Me, Me 397 A31

Me, Me 398 A31

Me, Me 399 A31

Me, Me 400 A31

Me, Me 401 A31

Me, Me 402 A31

Me, Me 403 A31

Me, Me 404 A31

Me, Me 405 A31

Me, Me 406 A31

Me, Me 407 A31

Me, Me 408 A31

Me, Me 409 A31

Me, Me 410 A31

Me, Me 411 A31

Me, Me 412 A31

Me, Me 413 A31

Me, Me 414 A31

Me, Me 415 A31

Me, Me 416 A31

Me, Me 417 A31

Me, Me 418 A31

Me, Me 419 A31

Me, Me 420 A31

Me, Me 421 A31

Me, Me 422 A31

Me, Me 423 A31

Me, Me 424 A31

Me, Me 425 A31

Me, Me 426 A31

Me, Me 427 A31

Me, Me 428 A31

Me, Me 429 A31

Me, Me 430 A31

Me, Me 431 A31

Me, Me 432 A31

Me, Me 433 A31

Me, Me 434 A31

Me, Me 435 A31

Me, Me 436 A31

Me, Me 437 A31

Me, Me 438 A31

Me, Me 439 A31

Me, Me 440 A31

Me, Me 441 A31

Me, Me 442 A31

Me, Me 443 A31

Me, Me 444 A31

Me, Me 445 A31

Me, Me 446 A31

Me, Me 447 A31

Me, Me 448 A31

Me, Me 449 A31

Me, Me 450 A31

Me, Me 451 A31

Me, Me 452 A31

Me, Me 453 A31

Me, Me 454 A31

Me, Me 455 A31

Me, Me 456 A31

Me, Me 457 A31

Me, Me 458 A31

Me, Me 459 A31

Me, Me 460 A31

Me, Me 461 A31

Me, Me 462 A31

Me, Me 463 A31

Me, Me 464 A31

Me, Me 465 A31

Me, Me 466 A31

Me, Me 467 A31

Me, Me 468 A31

Me, Me 469 A31

Me, Me 470 A31

Me, Me 471 A31

Me, Me 472 A31

Me, Me 473 A31

Me, Me 474 A31

Me, Me 475 A31

Me, Me 476 A31

Me, Me 477 A31

Me, Me 478 A31

Me, Me 479 A31

Me, Me 480 A31

Me, Me 481 A31

Me, Me 482 A31

Me, Me 483 A31

Me, Me 484 A31

Me, Me 485 A31

Me, Me 486 A31

Me, Me 487 A31

Me, Me 488 A31

Me, Me 489 A31

Me, Me 490 A31

Me, Me 491 A31

Me, Me 492 A31

Me, Me 493 A29

-cyclopropyl- 494 A29

-cyclopropyl- 495 A29

-cyclopropyl- 496 A29

-cyclopropyl- 497 A29

-cyclopropyl- 498 A29

-cyclopropyl- 499 A29

-cyclopropyl- 500 A29

-cyclopropyl- 501 A29

-cyclopropyl- 502 A29

-cyclopropyl- 503 A29

-cyclopropyl- 504 A29

-cyclopropyl- 505 A29

-cyclopropyl- 506 A29

-cyclopropyl- 507 A29

-cyclopropyl- 508 A29

-cyclopropyl- 509 A29

-cyclopropyl- 510 A29

-cyclopropyl- 511 A29

-cyclopropyl- 512 A29

-cyclopropyl- 513 A29

-cyclopropyl- 514 A29

-cyclopropyl- 515 A29

-cyclopropyl- 516 A29

-cyclopropyl- 517 A29

-cyclopropyl- 518 A29

-cyclopropyl- 519 A29

-cyclopropyl- 520 A29

-cyclopropyl- 521 A29

-cyclopropyl- 522 A29

-cyclopropyl- 523 A29

-cyclopropyl- 524 A29

-cyclopropyl- 525 A29

-cyclopropyl- 526 A29

-cyclopropyl- 527 A29

-cyclopropyl- 528 A29

-cyclopropyl- 529 A29

-cyclopropyl- 530 A29

-cyclopropyl- 531 A29

-cyclopropyl- 532 A29

-cyclopropyl- 533 A29

-cyclopropyl- 534 A29

-cyclopropyl- 535 A29

-cyclopropyl- 536 A29

-cyclopropyl- 537 A29

-cyclopropyl- 538 A29

-cyclopropyl- 539 A29

-cyclopropyl- 540 A29

-cyclopropyl- 541 A29

-cyclopropyl- 542 A29

-cyclopropyl- 543 A29

-cyclopropyl- 544 A29

-cyclopropyl- 545 A29

-cyclopropyl- 546 A29

-cyclopropyl- 547 A29

-cyclopropyl- 548 A29

-cyclopropyl- 549 A29

-cyclopropyl- 550 A29

-cyclopropyl- 551 A29

-cyclopropyl- 552 A29

-cyclopropyl- 553 A29

-cyclopropyl- 554 A29

-cyclopropyl- 555 A29

-cyclopropyl- 556 A29

-cyclopropyl- 557 A29

-cyclopropyl- 558 A29

-cyclopropyl- 559 A29

-cyclopropyl- 560 A29

-cyclopropyl- 561 A29

-cyclopropyl- 562 A29

-cyclopropyl- 563 A29

-cyclopropyl- 564 A29

-cyclopropyl- 565 A29

-cyclopropyl- 566 A29

-cyclopropyl- 567 A29

-cyclopropyl- 568 A29

-cyclopropyl- 569 A29

-cyclopropyl- 570 A29

-cyclopropyl- 571 A29

-cyclopropyl- 572 A29

-cyclopropyl- 573 A29

-cyclopropyl- 574 A29

-cyclopropyl- 575 A29

-cyclopropyl- 576 A29

-cyclopropyl- 577 A29

-cyclopropyl- 578 A29

-cyclopropyl- 579 A29

-cyclopropyl- 580 A29

-cyclopropyl- 581 A29

-cyclopropyl- 582 A29

-cyclopropyl- 583 A29

-cyclopropyl- 584 A29

-cyclopropyl- 585 A29

-cyclopropyl- 586 A29

-cyclopropyl- 587 A29

-cyclopropyl- 588 A29

-cyclopropyl- 589 A29

-cyclopropyl- 590 A29

-cyclopropyl- 591 A29

-cyclopropyl- 592 A29

-cyclopropyl- 593 A29

-cyclopropyl- 594 A29

-cyclopropyl- 595 A29

-cyclopropyl- 596 A29

-cyclopropyl- 597 A29

-cyclopropyl- 598 A29

-cyclopropyl- 599 A29

-cyclopropyl- 600 A29

-cyclopropyl- 601 A29

-cyclopropyl- 602 A29

-cyclopropyl- 603 A29

-cyclopropyl- 604 A29

-cyclopropyl- 605 A29

-cyclopropyl- 606 A29

-cyclopropyl- 607 A29

-cyclopropyl- 608 A29

-cyclopropyl- 609 A29

-cyclopropyl- 610 A29

-cyclopropyl- 611 A29

-cyclopropyl- 612 A29

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Dosage and Administration

The present disclosure includes pharmaceutical composition for treatinga subject having a neurological disorder comprising a therapeuticallyeffective amount of a compound of Formula (I), a derivative or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient, carrier or diluent.

The pharmaceutical compositions can be administered in a variety ofdosage forms including, but not limited to, a solid dosage form or in aliquid dosage form, an oral dosage form, a parenteral dosage form, anintranasal dosage form, a suppository, a lozenge, a troche, buccal, acontrolled release dosage form, a pulsed release dosage form, animmediate release dosage form, an intravenous solution, a suspension orcombinations thereof. The dosage can be an oral dosage form that is acontrolled release dosage form. The oral dosage form can be a tablet ora caplet. The compounds can be administered, for example, by oral orparenteral routes, including intravenous, intramuscular,intraperitoneal, subcutaneous, transdermal, airway (aerosol), rectal,vaginal and topical (including buccal and sublingual) administration. Inone embodiment, the compounds or pharmaceutical compositions comprisingthe compounds are delivered to a desired site, such as the brain, bycontinuous injection via a shunt.

In another embodiment, the compound can be administered parenterally,such as intravenous (IV) administration. The formulations foradministration will commonly comprise a solution of the compound of theFormula (I) dissolved in a pharmaceutically acceptable carrier. Amongthe acceptable vehicles and solvents that can be employed are water andRinger's solution, an isotonic sodium chloride. In addition, sterilefixed oils can conventionally be employed as a solvent or suspendingmedium. For this purpose any bland fixed oil can be employed includingsynthetic mono- or diglycerides. In addition, fatty acids such as oleicacid can likewise be used in the preparation of injectables. Thesesolutions are sterile and generally free of undesirable matter. Theseformulations may be sterilized by conventional, well known sterilizationtechniques. The formulations may contain pharmaceutically acceptableauxiliary substances as required to approximate physiological conditionssuch as pH adjusting and buffering agents, toxicity adjusting agents,e.g., sodium acetate, sodium chloride, potassium chloride, calciumchloride, sodium lactate and the like. The concentration of compound ofFormula (I) in these formulations can vary widely, and will be selectedprimarily based on fluid volumes, viscosities, body weight, and thelike, in accordance with the particular mode of administration selectedand the patient's needs. For IV administration, the formulation can be asterile injectable preparation, such as a sterile injectable aqueous oroleaginous suspension. This suspension can be formulated according tothe known art using those suitable dispersing or wetting agents andsuspending agents. The sterile injectable preparation can also be asterile injectable solution or suspension in a nontoxicparenterally-acceptable diluent or solvent, such as a solution of1,3-butanediol.

In one embodiment, a compound of Formula (I) can be administered byintroduction into the central nervous system of the subject, e.g., intothe cerbrospinal fluid of the subject. The formulations foradministration will commonly comprise a solution of the compound ofFormula (I) dissolved in a pharmaceutically acceptable carrier. Incertain aspects, the compound of Formula (I) is introducedintrathecally, e.g., into a cerebral ventricle, the lumbar area, or thecisterna magna. In another aspect, the compound of Formula (I) isintroduced intraocularly, to thereby contact retinal ganglion cells.

The pharmaceutically acceptable formulations can easily be suspended inaqueous vehicles and introduced through conventional hypodermic needlesor using infusion pumps. Prior to introduction, the formulations can besterilized with, preferably, gamma radiation or electron beamsterilization.

In one embodiment, the pharmaceutical composition comprising a compoundof Formula (I) is administered into a subject intrathecally. As usedherein, the term “intrathecal administration” is intended to includedelivering a pharmaceutical composition comprising a compound of Formula(I) directly into the cerebrospinal fluid of a subject, by techniquesincluding lateral cerebroventricular injection through a burrhole orcisternal or lumbar puncture or the like (described in Lazorthes et al.Advances in Drug Delivery Systems and Applications in Neurosurgery,143-192 and Omaya et al., Cancer Drug Delivery, 1: 169-179, the contentsof which are incorporated herein by reference). The term “lumbar region”is intended to include the area between the third and fourth lumbar(lower back) vertebrae. The term “cisterna magna” is intended to includethe area where the skull ends and the spinal cord begins at the back ofthe head. The term “cerebral ventricle” is intended to include thecavities in the brain that are continuous with the central canal of thespinal cord. Administration of a compound of Formula (I) to any of theabove mentioned sites can be achieved by direct injection of thepharmaceutical composition comprising the compound of Formula (I) or bythe use of infusion pumps. For injection, the pharmaceuticalcompositions can be formulated in liquid solutions, preferably inphysiologically compatible buffers such as Hank's solution or Ringer'ssolution. In addition, the pharmaceutical compositions may be formulatedin solid form and re-dissolved or suspended immediately prior to use.Lyophilized forms are also included. The injection can be, for example,in the form of a bolus injection or continuous infusion (e.g., usinginfusion pumps) of pharmaceutical composition.

In one embodiment, the pharmaceutical composition comprising a compoundof Formula (I) is administered by lateral cerebro ventricular injectioninto the brain of a subject. The injection can be made, for example,through a burr hole made in the subject's skull. In another embodiment,the encapsulated therapeutic agent is administered through a surgicallyinserted shunt into the cerebral ventricle of a subject. For example,the injection can be made into the lateral ventricles, which are larger,even though injection into the third and fourth smaller ventricles canalso be made.

In yet another embodiment, the pharmaceutical composition isadministered by injection into the cisterna magna, or lumbar area of asubject.

For oral administration, the compounds will generally be provided inunit dosage forms of a tablet, pill, dragee, lozenge or capsule; as apowder or granules; or as an aqueous solution, suspension, liquid, gels,syrup, slurry, etc. suitable for ingestion by the patient. Tablets fororal use may include the active ingredients mixed with pharmaceuticallyacceptable excipients such as inert diluents, disintegrating agents,binding agents, lubricating agents, sweetening agents, flavoring agents,coloring agents and preservatives. Suitable inert diluents includesodium and calcium carbonate, sodium and calcium phosphate, and lactose,while corn starch and alginic acid are suitable disintegrating agents.Binding agents may include starch and gelatin, while the lubricatingagent, if present, will generally be magnesium stearate, stearic acid ortalc. If desired, the tablets may be coated with a material such asglyceryl monostearate or glyceryl distearate, to delay absorption in thegastrointestinal tract.

Pharmaceutical preparations for oral use can be obtained throughcombination of a compound of Formula (I) with a solid excipient,optionally grinding a resulting mixture, and processing the mixture ofgranules, after adding suitable additional compounds, if desired, toobtain tablets or dragee cores. Suitable solid excipients in addition tothose previously mentioned are carbohydrate or protein fillers thatinclude, but are not limited to, sugars, including lactose, sucrose,mannitol, or sorbitol; starch from corn, wheat, rice, potato, or otherplants; cellulose such as methyl cellulose,hydroxypropylmethyl-cellulose or sodium carboxymethylcellulose; and gumsincluding arabic and tragacanth; as well as proteins such as gelatin andcollagen. If desired, disintegrating or solubilizing agents may beadded, such as the cross-linked polyvinyl pyrrolidone, agar, alginicacid, or a salt thereof, such as sodium alginate.

Capsules for oral use include hard gelatin capsules in which the activeingredient is mixed with a solid diluent, and soft gelatin capsuleswherein the active ingredients is mixed with water or an oil such aspeanut oil, liquid paraffin or olive oil.

Dragee cores are provided with suitable coatings. For this purpose,concentrated sugar solutions may be used, which may optionally containgum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethyleneglycol, and/or titanium dioxide, lacquer solutions, and suitable organicsolvents or solvent mixtures. Dyestuffs or pigments may be added to thetablets or dragee coatings for identification or to characterizedifferent combinations of active compound doses.

For transmucosal administration (e.g., buccal, rectal, nasal, ocular,etc.), penetrants appropriate to the barrier to be permeated are used inthe formulation. Such penetrants are generally known in the art.

Formulations for rectal administration may be presented as a suppositorywith a suitable base comprising for example cocoa butter or asalicylate. Formulations suitable for vaginal administration may bepresented as pessaries, tampons, creams, gels, pastes, foams or sprayformulations containing in addition to the active ingredient suchcarriers as are known in the art to be appropriate. For intramuscular,intraperitoneal, subcutaneous and intravenous use, the compounds willgenerally be provided in sterile aqueous solutions or suspensions,buffered to an appropriate pH and isotonicity. Suitable aqueous vehiclesinclude Ringer's solution and isotonic sodium chloride. Aqueoussuspensions may include suspending agents such as cellulose derivatives,sodium alginate, polyvinyl-pyrrolidone and gum tragacanth, and a wettingagent such as lecithin. Suitable preservatives for aqueous suspensionsinclude ethyl and n-propyl p-hydroxybenzoate.

The suppositories for rectal administration of the drug can be preparedby mixing the drug with a suitable non-irritating excipient which issolid at ordinary temperatures but liquid at the rectal temperatures andwill therefore melt in the rectum to release the drug. Such materialsare cocoa butter and polyethylene glycols.

The compounds can be delivered transdermally, by a topical route,formulated as applicator sticks, solutions, suspensions, emulsions,gels, creams, ointments, pastes, jellies, paints, powders, or aerosols.

The compounds may also be presented as aqueous or liposome formulations.Aqueous suspensions can contain a compound of Formula (I) in admixturewith excipients suitable for the manufacture of aqueous suspensions.Such excipients include a suspending agent, such as sodiumcarboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia,and dispersing or wetting agents such as a naturally occurringphosphatide (e.g., lecithin), a condensation product of an alkyleneoxide with a fatty acid (e.g., polyoxyethylene stearate), a condensationproduct of ethylene oxide with a long chain aliphatic alcohol (e.g.,heptadecaethylene oxycetanol), a condensation product of ethylene oxidewith a partial ester derived from a fatty acid and a hexitol (e.g.,polyoxyethylene sorbitol mono-oleate), or a condensation product ofethylene oxide with a partial ester derived from fatty acid and ahexitol anhydride (e.g., polyoxyethylene sorbitan monooleate). Theaqueous suspension can also contain one or more preservatives such asethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one ormore flavoring agents and one or more sweetening agents, such assucrose, aspartame or saccharin. Formulations can be adjusted forosmolarity.

Oil suspensions can be formulated by suspending a compound of Formula(I) in a vegetable oil, such as arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin; or a mixtureof these. The oil suspensions can contain a thickening agent, such asbeeswax, hard paraffin or cetyl alcohol. Sweetening agents can be addedto provide a palatable oral preparation, such as glycerol, sorbitol orsucrose. These formulations can be preserved by the addition of anantioxidant such as ascorbic acid. As an example of an injectable oilvehicle, see Minto, J. Pharmacol. Exp. Ther. 281:93-102, 1997. Thepharmaceutical formulations can also be in the form of oil-in-wateremulsions. The oily phase can be a vegetable oil or a mineral oil,described above, or a mixture of these. Suitable emulsifying agentsinclude naturally-occurring gums, such as gum acacia and gum tragacanth,naturally occurring phosphatides, such as soybean lecithin, esters orpartial esters derived from fatty acids and hexitol anhydrides, such assorbitan mono-oleate, and condensation products of these partial esterswith ethylene oxide, such as polyoxyethylene sorbitan mono-oleate. Theemulsion can also contain sweetening agents and flavoring agents, as inthe formulation of syrups and elixirs. Such formulations can alsocontain a demulcent, a preservative, or a coloring agent.

In addition to the formulations described previously, the compounds mayalso be formulated as a depot preparation. Such long acting formulationsmay be administered by implantation or transcutaneous delivery (e.g.,subcutaneously or intramuscularly), intramuscular injection or atransdermal patch. Thus, for example, the compounds may be formulatedwith suitable polymeric or hydrophobic materials (e.g., as an emulsionin an acceptable oil) or ion exchange resins, or as sparingly solublederivatives, for example, as a sparingly soluble salt.

The pharmaceutical compositions also may comprise suitable solid or gelphase carriers or excipients. Examples of such carriers or excipientsinclude but are not limited to calcium carbonate, calcium phosphate,various sugars, starches, cellulose derivatives, gelatin, and polymerssuch as polyethylene glycols.

For administration by inhalation, the compounds are convenientlydelivered in the form of an aerosol spray presentation from pressurizedpacks or a nebulizer, with the use of a suitable propellant, e.g.,dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In thecase of a pressurized aerosol the dosage unit may be determined byproviding a valve to deliver a metered amount. Capsules and cartridgesof e.g., gelatin for use in an inhaler or insufflator may be formulatedcontaining a powder mix of the compound and a suitable powder base suchas lactose or starch.

In general a suitable dose will be in the range of 0.01 to 100 mg perkilogram body weight of the recipient per day, preferably in the rangeof 0.1 to 10 mg per kilogram body weight per day. The desired dose ispreferably presented once daily, but may be dosed as two, three, four,five, six or more sub-doses administered at appropriate intervalsthroughout the day.

The compounds can be administered as the sole active agent, or incombination with other known therapeutics to be beneficial in thetreatment of neurological disorders. In any event, the administeringphysician can provide a method of treatment that is prophylactic ortherapeutic by adjusting the amount and timing of drug administration onthe basis of observations of one or more symptoms (e.g., motor orcognitive function as measured by standard clinical scales orassessments) of the disorder being treated.

Details on techniques for formulation and administration are welldescribed in the scientific and patent literature, see, e.g., the latestedition of Remington's Pharmaceutical Sciences, Maack Publishing Co,Easton Pa. After a pharmaceutical composition has been formulated in anacceptable carrier, it can be placed in an appropriate container andlabeled for treatment of an indicated condition. For administration ofthe compounds of Formula (I), such labeling would include, e.g.,instructions concerning the amount, frequency and method ofadministration.

Biological Examples In Vivo Methods

Subjects: Male C57BL/6J mice (Charles River; 20-25 g) were used for allassays except prepulse inhibition (PPI) which used male DBA/2N mice(Charles River, 20-25 g). For all studies, animals were housed five/cageon a 12-h light/dark cycle with food and water available ad libitum.

Conditioned avoidance responding: Testing was performed in commerciallyavailable avoidance boxes (Kinder Scientific, Poway Calif.). The boxeswere divided into two compartments separated by an archway. Each side ofthe chamber has electronic grid flooring that is equipped to administerfootshocks and an overhead light. Training consisted of repeatedpairings of the light (conditioned stimulus) followed by a shock(unconditioned stimulus). For each trial the light was presented for 5sec followed by a 0.5 mA shock that would terminate if the mouse crossedto the other chamber or after 10 seconds. The intertrial interval wasset to 20 seconds. Each training and test session consisted a four minhabituation period followed by 30 trials. The number of avoidances(mouse crossed to other side during presentation of the light), escapes(mouse crossed to the other side during presentation of the shock) andfailures (mouse did not cross during the entire trial period) wererecorded by a computer. For study inclusion an animal had to reach acriterion of at least 80% avoidances for two consecutive test sessions.

PPI: Mice were individually placed into the test chambers(StartleMonitor, Kinder Scientific, Poway Calif.). The animals weregiven a five min acclimation period to the test chambers with thebackground noise level set to 65 decibel (dB) which remained for theentire test session. Following acclimation, four successive trials 120dB pulse for 40 msec were presented, however these trials were notincluded in data analysis. The mice were then subjected to fivedifferent types of trials in random order: pulse alone (120 dB for 40msec), no stimulus and three different prepulse+pulse trials with theprepulse set at 67, 69 or 74 dB for 20 msec followed a 100 msec later bya 120 dB pulse for 40 msec. Each animal received 12 trials for eachcondition for a total of 60 trials with an average intertrial intervalof 15 sec. Percent PPI was calculated according to the followingformula: (1−(startle response to prepulse+pulse)/startle response topulse alone))×100.

MK-801-induced hyperactivity: After a 30 min acclimatation to the testroom mice were individually placed into test cages for a 30 minhabituation period. Following habituation to test cages, baselineactivity was recorded for 60 min. Mice were then briefly removed andadministered test compound and placed immediately back into the testcage. At 5 min prior to test time mice were again briefly removed fromtest cages and administered MK-801 (0.3 mg/kg, i.p. in 0.9% saline) andthen immediately placed back into test cages and activity level recorded1 hour. Activity level was measured as distance travelled in centimeters(Ethovision tracking software, Noldus Inc. Wageningen, Netherlands).

Catalepsy: Mice were placed on a wire mesh screen set at a 60 degreeangle with their heads facing upwards and the latency to move or breakstance was recorded. Animals were given three trials per time point witha 30 sec cut-off per trial.

Data analysis: A one-way or two-way ANOVA was used to evaluate overalldifferences between treatments and a Tukey's post-hoc test or Student'st-test was used to evaluate differences between treatment groups for theone-way ANOVA and a Bonferroni test was used for the two-way ANOVA. Thecriterion for statistical significance was set to p≦0.05.

In Vitro Methods

hPDE10A1 Enzyme Activity: 50 μl samples of serially diluted HumanPDE10A1 enzyme were incubated with 50 μl of [³H]-cAMP for 20 minutes (at37° C.). Reactions were carried out in Greiner 96 deep well 1 mlmaster-block. The enzyme was diluted in 20 mM Tris HCl pH7.4 and[³H]-cAMP was diluted in 10 mM MgCl₂, 40 mM Tris.HCl pH 7.4. Thereaction was terminated by denaturing the PDE enzyme (at 70° C.) afterwhich [³H]-5′-AMP was converted to [³H]-adenosine by adding 25 μl snakevenom nucleotidase and incubating for 10 minutes (at 37° C.). Adenosine,being neutral, was separated from charged cAMP or AMP by the addition of200 μl Dowex resin. Samples were shaken for 20 minutes then centrifugedfor 3 minutes at 2,500 r.p.m. 50 μl of supernatant was removed and addedto 200 μl of MicroScint-20 in white plates (Greiner 96-well Optiplate)and shaken for 30 minutes before reading on Perkin Elmer TopCountScintillation Counter.

hPDE10A1 Enzyme Inhibition: To check inhibition profile 11 μl ofserially diluted inhibitor was added to 50 μl of [³H]-cAMP and 50 ul ofdiluted Human PDE10A1 and assay was carried out as in the enzymeactivity assay. Data was analysed using Prism software (GraphPad Inc).Representative compounds of this disclosure are shown in the tablebelow. A compound with the value “A” had an IC₅₀ value less than orequal to 10 nM. A compound with the value “B” had an IC₅₀ value greaterthan 10 nM and less than 50 nM:

hPDE10A1 Name IC₅₀ Band4-(4-((3,5-dimethylpyridin-2-yl)methoxy)phenyl)-5-(4-methoxyphenyl)-2,2-A dimethylfuran-3(2H)-one4-(4-(imidazo[1,2-a]pyridin-2-ylmethoxy)phenyl)-5-(4-methoxyphenyl)-2,2-A dimethylfuran-3(2H)-one4-(4-(imidazo[1,2-b]pyridazin-6-ylmethoxy)phenyl)-5-(4-methoxyphenyl)- B2,2-dimethylfuran-3(2H)-one4-(4-((6-chloroimidazo[1,2-b]pyridazin-2-yl)methoxy)phenyl)-5-(4- Bmethoxyphenyl)-2,2-dimethylfuran-3(2H)-one4-(4-(imidazo[1,2-b]pyridazin-2-ylmethoxy)phenyl)-5-(4-methoxyphenyl)- A2,2-dimethylfuran-3(2H)-one4-(3-(4-(imidazo[1,2-a]pyridin-2-ylmethoxy)phenyl)-5,5-dimethyl-4-oxo-4,5-A dihydrofuran-2-yl)benzonitrile4-(4-((3-chloroimidazo[1,2-a]pyridin-2-yl)methoxy)phenyl)-5-(4- Amethoxyphenyl)-2,2-dimethylfuran-3(2H)-one5-(4-methoxyphenyl)-2,2-dimethyl-4-(4-((5-methylpyridin-2- Ayl)methoxy)phenyl)furan-3(2H)-one4-(5,5-dimethyl-3-(4-((5-methylpyridin-2-yl)methoxy)phenyl)-4-oxo-4,5- Adihydrofuran-2-yl)benzonitrile4-(4-((6-chloroimidazo[1,2-a]pyridin-2-yl)methoxy)phenyl)-5-(4- Amethoxyphenyl)-2,2-dimethylfuran-3(2H)-one5-(4-methoxyphenyl)-2,2-dimethyl-4-(4-((3-methylimidazo[1,2-a]pyridin-2-B yl)methoxy)phenyl)furan-3(2H)-one5-(4-methoxyphenyl)-2,2-dimethyl-4-(4-((5-methylimidazo[1,2-a]pyridin-2-A yl)methoxy)phenyl)furan-3(2H)-one

1.-35. (canceled)
 36. A method for treating a central nervous system(CNS) disorder comprising administering to a human in need thereof atherapeutically effective amount of4-(4-(imidazo[1,2-b]pyridazin-2-ylmethoxy)phenyl)-2,2-dimethyl-5-(pyridin-4-yl)furan-3(2H)-oneor a pharmaceutically acceptable salt thereof.
 37. The method of claim36, wherein the CNS disorder is one or more of Huntington's disease,schizophrenia, schizo-affective condition, delusional disorder,drug-induced psychosis, panic disorder, obsessive compulsive disorder,post-traumatic stress disorder, age-related cognitive decline, attentiondeficit/hyperactivity disorder, bipolar disorder, personality disorderof the paranoid type, personality disorder of the schizoid type,dyskinesia, choreiform condition, psychosis associated with Parkinson'sdisease, psychotic symptoms associated with Alzheimer's disease,dystonic condition, mood disorder, and dementia.
 38. The method of claim36, wherein the CNS disorder is schizophrenia, schizo-affectivecondition, Huntington's disease, bipolar disorder, obsessive compulsivedisorder, dystonic condition, or tardive dyskinesia.
 39. The method ofclaim 37, wherein the dementia is multi-infarct dementia, AIDS-relateddementia, or neurodegenerative dementia.
 40. The method of claim 36,wherein the CNS disorder is schizophrenia or schizo-affective condition.41. The method of claim 36, wherein the CNS disorder is Huntington'sdisease.
 42. The method of claim 36, wherein the CNS disorder is bipolardisorder.
 43. The method of claim 36, wherein the CNS disorder isobsessive compulsive disorder.
 44. A method for treating one or moreconditions chosen from an eating disorder, obesity, compulsive gambling,sexual disorder, narcolepsy, sleep disorder, diabetes, and metabolicsyndrome, or for smoking cessation treatment, comprising administeringto a human in need thereof a therapeutically effective amount of4-(4-(imidazo[1,2-b]pyridazin-2-ylmethoxy)phenyl)-2,2-dimethyl-5-(pyridin-4-yl)furan-3(2H)-oneor a pharmaceutically acceptable salt thereof.
 45. The method of claim44, wherein the condition is obesity or metabolic syndrome.
 46. A methodfor treating a CNS disorder comprising administering to a human in needthereof a therapeutically effective amount of a pharmaceuticalcomposition comprising: (i)4-(4-(imidazo[1,2-b]pyridazin-2-ylmethoxy)phenyl)-2,2-dimethyl-5-(pyridin-4-yl)furan-3(2H)-oneor a pharmaceutically acceptable salt thereof; and (ii) apharmaceutically acceptable carrier or excipient.
 47. The method ofclaim 46, wherein the CNS disorder is one or more of Huntington'sdisease, schizophrenia, schizo-affective condition, delusional disorder,drug-induced psychosis, panic disorder, obsessive compulsive disorder,post-traumatic stress disorder, age-related cognitive decline, attentiondeficit/hyperactivity disorder, bipolar disorder, personality disorderof the paranoid type, personality disorder of the schizoid type,dyskinesia, choreiform condition, psychosis associated with Parkinson'sdisease, psychotic symptoms associated with Alzheimer's disease,dystonic condition, mood disorder, and dementia.
 48. The method of claim46, wherein the CNS disorder is schizophrenia, schizo-affectivecondition, Huntington's disease, bipolar disorder, obsessive compulsivedisorder, dystonic condition, or tardive dyskinesia.
 49. The method ofclaim 47, wherein the dementia is multi-infarct dementia, AIDS-relateddementia, or neurodegenerative dementia.
 50. The method of claim 46,wherein the CNS disorder is schizophrenia or schizo-affective condition.51. The method of claim 46, wherein the CNS disorder is Huntington'sdisease.
 52. The method of claim 46, wherein the CNS disorder is bipolardisorder.
 53. The method of claim 46, wherein the CNS disorder isobsessive compulsive disorder.
 54. A method for treating one or moreconditions chosen from an eating disorder, obesity, compulsive gambling,sexual disorder, narcolepsy, sleep disorder, diabetes, metabolicsyndrome, or for smoking cessation treatment, comprising administeringto a human in need thereof a therapeutically effective amount of apharmaceutical composition comprising: (i)4-(4-(imidazo[1,2-b]pyridazin-2-ylmethoxy)phenyl)-2,2-dimethyl-5-(pyridin-4-yl)furan-3(2H)-oneor a pharmaceutically acceptable salt thereof; and (ii) apharmaceutically acceptable carrier or excipient.
 55. The method ofclaim 54, wherein the condition is obesity or metabolic syndrome.